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‘False-Positive’ and ‘False-Negative’ Test Results in Clinical Urine Drug Testing
Bioanalysis
Abstract
The terms 'false-positive' and 'false-negative' are widely used in discussions of urine drug test (UDT) results. These terms are inadequate because they are used in different ways by physicians and laboratory professionals and they are too narrow to encompass the larger universe of potentially misleading, inappropriate and unexpected drug test results. This larger universe, while not solely comprised of technically 'true' or 'false' positive or negative test results, presents comparable interpretive challenges with corresponding clinical implications. In this review, we propose the terms 'potentially inappropriate' positive or negative test results in reference to UDT results that are ambiguous or unexpected and subject to misinterpretation. Causes of potentially inappropriate positive UDT results include in vivo metabolic conversions of a drug, exposure to nonillicit sources of a drug and laboratory error. Causes of potentially inappropriate negative UDT results include limited assay specificity, absence of drug in the urine, presence of drug in the urine, but below established assay cutoff, specimen manipulation and laboratory error. Clinical UDT interpretation is a complicated task requiring knowledge of recent prescription, over-the-counter and herbal drug administration, drug metabolism and analytical sensitivities and specificities.
... In cases where the examined patients are under-age, they could be unjustly taken away from their parents [25]. In addition, this problem can cost a person their job, interfere with their sports qualifications, or lead to their exclusion from rehabilitation programs [27]. All these examples argue for the urgent focus of toxicological analysis on the most common sources of error in amphetamines' rapid drug screening. ...
... In general, incorrect drug screening results are classified as false positive and false negative. A false positive result is one in which the test incorrectly indicates the presence of a narcotic substance in the examined sample, and vice versa, a false negative is one in which the test incorrectly indicates the absence of the narcotic substance when it is actually present in the biological material [27]. ...
... The reason for this can also be the low specificity of immunoanalytical tests. It is related to the cases in which a given test cannot detect a substance of the same chemical class, which is especially important against the background of the constant spewing of new amphetamines [27]. Another possible reason could be low levels of the drug in the sample and the inability to exceed the cut-off concentration of the tests. ...
The need for toxicological screening of amphetamine users is growing in parallel with its increasing abuse. At the same time, it turns out that these substances most often give false results in rapid drug immunoassay. Therefore, the aim of the present work was to investigate the sources of false positive or false negative results. For this purpose, an analysis of the literature sources in the databases of Google Scholar, PubMed, and Science Direct, was made. The results showed that a number of prescription or OTC medications can cause false positive results due to cross-reactivity (ephedrine, pseudoephedrine, labetalol, metoprolol, some antidepressants, metformin, ranitidine, ofloxacin, selegiline, etc). In this regard, alternative medications for patients who often have to undergo such screening have been proposed. Some possibilities of unintentionally or intentionally inducing false negative results have also been highlighted. Popular approaches to fooling the screening test are diluting the urine, adding adulterants (marketed products or homemade chemicals), and providing foreign or synthetic urine. Summarizing the possible sources of errors in drug screening is expected to objectify the interpretation of the obtained results.
... The prescribing clinicians consulted the literature, which described potential false positive or false negative results that may be encountered using the UDT [19,21,22]. For example, consumption of substances such as methylphenidate, trazodone, tyramine, labetalol, propranolol, bupropion, ephedrine, and pseudoephedrine may all lead to a positive reading for an amphetamine [23]. If the UDT was positive for benzodiazepines, consumption of sertraline could lead to a false positive. ...
... All these can lead to false negative results. Details of substances that can potentially result in false positive and false negative results during clinical urine drug testing can be found elsewhere [23]. ...
Simple Summary
A urine drug test (UDT) is often used in the treatment of cancer pain to monitor compliance with opioid treatment. Two types of UDT are commonly for this purpose: the immunoassay test, and the mass spectrometry method. Only a few studies have examined the use of immunoassay UDT for cancer patients in palliative care clinics. In this study, we examined the frequency of immunoassay UDT abnormalities, and the factors associated with aberrant findings at a safety-net hospital palliative medicine clinic. Electronic medical records of 913 patients were reviewed. We found that 27% had aberrant UDT results; 35% of these were positive for cocaine. Non-Hispanic White race, history of illicit drug use, and history of marijuana use were associated with an aberrant finding. Despite limitations of immunoassay UDT, it could detect aberrant drug-taking behaviors in a significant number of patients. These findings support the utility of immunoassay UDT in clinical settings with less resources.
Abstract
Background: Few studies have examined the use of immunoassay urine drug testing of cancer patients in palliative care clinics. Objectives: We examined the frequency of immunoassay urine drug test (UDT) abnormalities and the factors associated with aberrancy at a safety-net hospital palliative medicine clinic. Methods: A retrospective review of the electronic medical records of consecutive eligible patients seen at the outpatient palliative medicine clinic in a resource-limited safety-net hospital system was conducted between 1 September 2015 and 31 December 2020. We collected longitudinal data on patient demographics, UDT findings, and potential predictors of aberrant results. Results: Of the 913 patients in the study, 500 (55%) underwent UDT testing, with 455 (50%) having the testing within the first three visits. Among those tested within the first three visits, 125 (27%) had aberrant UDT results; 44 (35%) of these 125 patients were positive for cocaine. In a multivariable regression model analysis of predictors for aberrant UDT within the first three visits, non-Hispanic White race (odds ratio (OR) = 2.13; 95% confidence interval (CI): 1.03–4.38; p = 0.04), history of illicit drug use (OR = 3.57; CI: 1.78–7.13; p < 0.001), and history of marijuana use (OR = 7.05; CI: 3.85–12.91; p < 0.001) were independent predictors of an aberrant UDT finding. Conclusion: Despite limitations of immunoassay UDT, it was able to detect aberrant drug-taking behaviors in a significant number of patients seen at a safety-net hospital palliative care clinic, including cocaine use. These findings support universal UDT monitoring and utility of immunoassay-based UDT in resource-limited settings.
... However, they also come with several limitations that make assessing prescription compliance challenging. For instance, drugs of abuse immunoassays are susceptible to false-positive results by crossreacting with compounds that are structurally or chemically similar to their target, such as some over-the-counter nasal decongestants or the prescription medication bupropion with many IVD amphetamine drug screens [12,13]. To determine whether the initial screening result was a true or false positive, confirmatory testing using an MS LDT is necessary. ...
... Immunoassays are prone to false-negative results due to the higher cutoffs for positivity set by IVD manufacturers compared to MS-based LDTs [12,15]. In clinical settings, cutoffs for many IVD drugs of abuse are an order of magnitude higher than the cutoff for MS-based LDTs [14,16]. ...
•Toxicology testing provides valuable information for patient management.•Current in vitro diagnostics (IVDs) are unable to meet all clinical needs.•Lab-developed tests (LDTs) in toxicology can be used to close clinical care gaps.•LDTs in clinical toxicology are almost exclusively mass spectrometry-based methods.
... False-positives may occur as the assay antibodies cross-react with structurally similar or structurally unrelated compounds. Numerous examples have been described [25,26]. In case of assays targeted towards a drug class, e.g. ...
... For example, the opiate assays sold by ThermoFisher Scientific (CEDIA methodology) and Roche Diagnostics (KIMS methodology) have a cross-reactivity with morphine-3-glucuronide of 94% and 54%, respectively. Analytical false-negatives due to interfering compounds are rarely reported [25]. One example is interference in EMIT II assays due to salicyluric acid, the principal urinary metabolite of salicylic acid, by reducing the molar absorptivity of NADH [31]. ...
This manuscript offers a broad overview of the state of emergency toxicology testing in clinical laboratories. We summarize the specific challenges of performing emergency toxicology testing, introduce a variety of currently used methods including mass spectrometry, and compare and contrast the utility of different types of mass spectrometers for this purpose. Finally, we examine evidence on the utility of toxicological testing in the treatment of poisoned patients, with special emphasis on the demonstrated utility of mass spectrometry-based tests. This review included primary literature indexed in the NCBI PubMed Database. Search terms included “emergency toxicology”, “emergency mass spectrometry”, “mass spectrometry toxicology”, “utility of toxicology testing”, and “toxicology surveillance”. There are relatively few clinical trials on the utility of toxicology testing in overdosed or poisoned patients, and those studies that exist have a number of limitations. One of the most significant is that nearly all were conducted with immunoassay-based tests, which can only detect a limited number of compounds and are known to have a high false-positive rate. In addition, few are prospective. The overwhelming majority of studies of immunoassay-based tests concluded that results rarely changed patient management, regardless of the patient’s clinical presentation. Many of these studies suggest that results could still be useful in other contexts, including identification of opportunities to refer a patient to substance abuse treatment or avoidance of drug-drug interactions. Mass spectrometry-based testing has several advantages over immunoassays, including the breadth of compounds that can be detected and substantially higher specificity, yet many questions remain about utility in emergency toxicology. The utility of mass spectrometry-based testing has not been assessed in a prospective clinical trial, rather the literature is overwhelmingly case-based, and a small number of laboratories are responsible for the majority of the case reports. The limited evidence that exists suggests that mass spectrometry can be useful in emergency situations, provided that results are available rapidly, interpreted by a knowledgeable physician, and that the scope of the method includes the compound implicated in the poisoning. Like results from immunoassays, many authors report using mass spectrometry-based testing for purposes other than direct patient care, namely surveillance of emerging drugs and trends in local drug use. A number of case reports and larger case series present evidence in support of this use. Despite the potential advantages of mass spectrometry, the quantity and quality of published evidence are not sufficient to adequately assess the utility of mass spectrometry-based emergency toxicology results. This is a field that is ripe for investigation, particularly as mass spectrometers become less expensive and the technology is adopted by an increasing number of clinical laboratories. There is a strong need for prospective studies on implementation of STAT mass spectrometry-based tests in emergency toxicology and larger scale assessments of impact on acute patient care as well as public health.
... At the same time, the use of immunoassays ('quick tests') for screening of drug use has increased considerably, particularly in the USA with an overall 14,000-fold increase and for general practice a 8700-fold increase during -2009(Collen 2012. However, this increase may even be underestimated as the data originate from specific procedural codes used to bill the United States Medicare and private insurance for medical procedures. ...
... While there may be good reasons to make rational use of immunoassays for various purposes, it is crucial that the strengths and limitations of these tests are fully acknowledged. Although immunoassays are relatively inexpensive, easy and practical to use, the limitations and intrinsic errors of this technique for drug testing have been known for decades, with numerous, published cases in the literature (Moeller et al. 2008;Reisfield et al. 2009;Saitman et al. 2014). Among the pitfalls immunoassays (1) do not identify the compounds that cause 'presumptive positive' results; (2) show 'false positives' due to cross reactions with medicines, food and drink ingredients or endogenous compounds; (3) are seldom documented properly in logbooks data and patient's medical records; (4) do not test for new psychoactive substances; (5) are often used by non-medically trained personnel; (6) are poorly understood and difficult to interpret even by healthcare professionals; and (7) are not systematically followed by confirmatory analysis because proper guidelines may not be implemented. ...
The use of medicines to treat attention deficit/hyperactivity disorder (ADHD) has increased worldwide, including the use of amphetamine-based medicines or prodrugs that metabolise to amphetamine in vivo. At the same time, drugs-of-abuse testing by non-specific, point-of-care immunoassay methods (‘quick tests’) has increased. This article discusses the risk of ‘false positive’ results or post-analytical misinterpretations of results when immunoassays are used to analyse biological samples from ADHD patients. A rapid evidence review was conducted to identify studies that have focused on the risk of ‘false positive’ test results in immunoassay testing of patients treated with atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil. There is only evidence to suggest that bupropion should cause ‘false positive’ immunoassay results. However, there is a lack of systematic, updated evaluations and validations of cross-reactivity patterns for immunoassays in the literature. Advanced laboratory methods can distinguish the use of medicines from illicit amphetamine by stereospecific analysis of dextro- and levoamphetamine; however, these analytical services are not commonly available for routine drug testing. The present situation calls for more awareness, proper education and information on these critical ethical issues in drug testing, both for clinicians, other healthcare professionals involved in drug testing and for patients in medical treatment for ADHD. The pitfalls of immunoassays due to cross-reactivity and insufficient specificity/sensitivity can have serious negative consequences for patients safety with regard to incorrect laboratory drug-testing results. Consequently, confirmatory laboratory analysis should always be performed for ‘presumptive’ positive immunoassay screening results.
... I t has been well-established that urine drug testing is an important component of treatment plans for patients on chronic opioid therapy (1)(2)(3)(4)(5)(6). Much has been written about false-positive results (7,8), however in the clinical setting, false-negative results are just as important (8). Physicians monitoring patients on chronic opioid therapy presume that the cutoffs provided by their laboratory are like those reference intervals for specific analytes to establish possible health and disease states of a patient (9)(10)(11). ...
... I t has been well-established that urine drug testing is an important component of treatment plans for patients on chronic opioid therapy (1)(2)(3)(4)(5)(6). Much has been written about false-positive results (7,8), however in the clinical setting, false-negative results are just as important (8). Physicians monitoring patients on chronic opioid therapy presume that the cutoffs provided by their laboratory are like those reference intervals for specific analytes to establish possible health and disease states of a patient (9)(10)(11). ...
Background:
Urine drug testing is used by health care providers to determine a patient's compliance to their prescribed regimen and to detect non-prescribed medications and illicit drugs. However, the cutoff levels used by clinical labs are often arbitrarily set and may not reflect the urine drug concentrations of compliant patients.
Objectives:
Our aim was to test the hypothesis that commonly used cutoffs for many prescribed and illicit drugs were set too high, and methods using these cutoffs may yield a considerable number of false-negative results. The goals of this study were to outline the way to analyze patient results and estimate a more appropriate cutoff, develop and validate a high sensitivity analytical method capable of quantitating drugs and metabolites at lower than the commonly used cutoffs, and determine the number of true positive results that would have been missed when using the common cutoffs.
Study design:
This was a retrospective study of urine specimens submitted for urine drug testing as part of the monitoring of prescription drug compliance described in chronic opioid therapy treatment guidelines.
Setting:
The study was set in a clinical toxicology laboratory, using specimens submitted for routine analysis by health care providers in the normal course of business.
Methods:
Lognormal distributions of test results were generated and fitted with a trendline to estimate the required cutoff level necessary to capture the normal distributions of each drug for the patient population study. A validated laboratory derived liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis capable of achieving the required cutoff levels was developed for each drug and/or metabolite.
Results:
The study shows that a lognormal distribution of patient urine test results fitted with a trendline is appropriate for estimating the required cutoff levels needed to assess medication adherence. The study showed a wide variation in the false-negative rate, ranging from 1.5% to 94.3% across a range of prescribed and illicit drugs.
Limitations:
The patient specimens were largely sourced from patients in either a long-term pain management program or in treatment for substance use disorder in the US. These specimens may not be representative of patients in other types of treatment or in countries with different approaches to these issues.
Conclusions:
The high-sensitivity method reduces false-negative results which could negatively impact patient care. Clinicians using less sensitive methods for detecting and quantifying drugs and metabolites in urine should exercise caution in assessing patient adherence using and changing the treatment plan based on those results.
Key words:
Urine drug testing, patient adherence, clinical toxicology, immunoassay, LC-MS, definitive drug testing, REMS, negative test results, false negative.
... -58 Although physicians often obtain standard urine drug screens in the workup of suspected opioid ingestion, they have a significant false negative rate. A negative urine drug screen does not exclude the possibility of opioid toxicity.[59][60][61][62] Notably, there are various extended drug screens available that will assess for the presence of a greater number of substances. ...
Recent increases in pediatric and adolescent opioid fatalities mandate an urgent need for early consideration of possible opioid exposure and specific diagnostic and management strategies and interventions tailored to these unique populations. In contrast to adults, pediatric methods of exposure include accidental ingestions, prescription misuse, and household exposure. Early recognition, appropriate diagnostic evaluation, along with specialized treatment for opioid toxicity in this demographic are discussed. A key focus is on Naloxone, an essential medication for opioid intoxication, addressing its unique challenges in pediatric use. Unique pediatric considerations include recognition of accidental ingestions in our youngest population, critical social aspects including home safety and intentional exposure, and harm reduction strategies, mainly through Naloxone distribution and education on safe medication practices. It calls for a multifaceted approach, including creating pediatric‐specific guidelines, to combat the opioid crisis among children and to work to lower morbidity and mortality from opioid overdoses.
... Ключови думи: Канабис, марихуана, пасивно пушене, токсикохимичен анализ цински цели, както и при контрола на наркотичната злоупотреба сред населението. Необходимост от такъв тип изследвания може да възникне при шофьори; на работното място при хора, чиито професии изискват висока концентрация и внимание; при спортисти; при лица участващи в рехабилитационни програми и други (17,35). В практиката токсикохимичният анализ на наркотични вещества се осъществява чрез последователно протичащи скринингови и доказателствени методи. ...
Cannabis continues to be the most widely used drug worldwide. This increases the risk of positive drug tests in individuals with a secondary exposure. For this reason , the aim of the present work was to clarify the possibilities of modern toxicochemical analysis to distinguish the biological samples of passive smokers of cannabis. The algorithm by which drug use is monitored today includes the sequential implementation of screening and evidentiary analytical methods. Through the former, possible drug users are filtered, and through the latter, the reliability of the obtained results is categorically confirmed. Due to its kinetic characteristics, the main psycho-active component of marijuana, Δ9-tetrahydrocan-nabinol (THC), is sometimes replaced as a target an-alyte by one of its metabolites. In urine, which is the most frequently studied type of biological matrix, it is practice to determine the amount of non-pharmacologically active 11-nor-9-carboxy-Δ9-tetrahydrocan-binol. It has been established that in passive smokers its concentrations do not exceed 50 ng/mL in drug screening and 15 ng/mL in confirmatory analysis. Alternatively , THC and/or its metabolites can be tested in blood, hair, saliva, and others. The analytical tools of the XXI century allow the identification of individuals exposed to the psychoac-tive agent THC in a passive way. This does not, however , negate the personal responsibility of each individual to avoid playing the role of a passive smoker.
... Drug metabolism, effects of the genetics and environment on drug metabolism, and the advantages and limitations of each detection method are all important in interpreting UDT results. The terms "false positive" and "false negative" are widely used in UDT and insufficiently describe the results because they are used in different ways by medical practitioners and laboratory specialists [90]. Therefore, the test results can be broadly described as follows: Numerous drugs can interfere with (in vivo or in vitro) laboratory tests. ...
Various definitions can be considered for drugs and substance abuse. According to the National Institute on Abuse, the use of an over-the-counter drug in a different way than that prescribed to experience or arouse emotion is a simple form of drug abuse. The World Health Organization (WHO) also defines drug abuse as the persistent or sporadic use of drugs that are incompatible or unrelated to acceptable medical practice. With the increasing non-therapeutic use of prescription drugs, serious related consequences have also increased. Therefore, there is a need to know more precisely about the types of substances and drug abuse, which is the most important part of diagnosis and recognizing the tests that cause false positive and negative results. The purpose of this review article is to collect and summarize the most important and more common types of drugs of abuse and review the drugs that cause false results in screening tests. In addition, the most common detection methods of the drug will be reviewed and the advantages and drawbacks of each method will be discussed. In this article, we aimed to point out all the facts about the emerging problems in drug abuse, the methods of screening, and the possible false results in addition to troubleshooting strategies.
... Pre-analytic errors include incorrect labeling of a specimen, incorrect ordering of a test, use of a wrong container for collection, or adulteration of a specimen. 52 Analytical errors include assay cross-reaction with a pharmacologically or structurally unrelated molecule or impaired binding of the antigen (drug or metabolite) to the detection antibody. Post-analytical errors are logistical errors such as incorrect interpretation of a test result such as considering a result positive despite the quantitative level falling below the threshold required for a positive result. ...
Diversion of substances from the care of the intended patient is a significant problem in healthcare. Patients are harmed by the undertreatment of pain and suffering, transmission of disease, as well as the risk associated with impaired vigilance. Healthcare providers may be harmed by the physical and mental impact of their addictions. Healthcare systems are placed in jeopardy by the legal impact associated with illegal routes of drug release including sanction and financial liability and loss of public trust. Healthcare institutions have implemented many measures to reduce diversion from the perioperative area. These efforts include education, medical record surveillance, automated medication dispensing systems, urine drug testing, substance waste management systems, and drug diversion prevention teams. This narrative review evaluates strengths, weaknesses, and effectiveness of these systems and provides recommendations for leaders and care providers.
... In most cases drug tests are specific, and the number of potentially interfering substances is relatively low; however, amphetamine is an exception, for which the largest number of interfering substances was recorded [17,20]. For these reasons, the assessment of the specificity of the immersion tests was an important part of current study, even if it was conducted only for three different compounds. ...
Citation: Miłos, A.; Gackowski, M.; Przybylska, A.; Kośliński, P.; Koba, M. Comparison of Sensitivity and Specificity of Commercial Amphetamine Tests. AppliedChem 2023, 3, 141-152. https://doi. Abstract: Drug addiction is a disease that is characterized by a compulsion, a desire to take different substances permanently or for a certain period of time. Numerous negative incidents, such as crimes, work accidents and traffic accidents, are related to using illegal substances. Therefore, urine drug cassette tests have become a screening tool. However, considering legal consequences of test result, the question arises of their performance and reliability. On this account, the main objective of this study was to evaluate the sensitivity and specificity of urine drug tests available on the commercial pharmaceutical market. Evaluated tests were immersed in synthetic urine diluent spiked with amphetamine at various concentrations also containing potentially interfering substances such as caffeine, paracetamol and acetylsalicylic acid, and after a certain period of time, it was observed whether the result was as expected. The reference method used in this study was high-performance liquid chromatography. The obtained results confirmed the declared cutoff as well as specificity of rapid diagnostic tests.
... For ease of referencing results that are directly responsive to the study question, those for which codeine concentrations ≥300 ng/mL were coupled with morphine concentrations <300 ng/mL have been bolded. No samples were positive for hydrocodone or hydromorphone, minor metabolites of codeine and morphine, respectively (data not shown) (33). ...
Consumption of poppy seed-containing food products can result in opiate-positive urine drug test results and may pose challenges in distinguishing poppy seed consumption from opiate administration. In this context, guidance has suggested that codeine concentrations exceeding 300 ng/mL coupled with morphine-to-codeine ratios <2 are indicative of codeine consumption and, therefore, exclude poppy seed consumption as a legitimate explanation for the test result. In recent years, we performed independent medical examinations of three individuals who produced codeine-positive/morphine negative (300 ng/mL) forensic urine drug test results, and who denied codeine administration, attributing their test results to the consumption of specific poppy seed-containing food products. In the present study, 11 participants consumed one of 10 unique poppy seed-containing food products, including the three implicated food products. Six of 33 non-baseline urine samples (18%) - representing three food products - were positive for codeine and negative for morphine at 300 ng/mL cutoffs (and, therefore featured morphine-to-codeine ratios <2). This study adds to a small literature indicating that consumption of poppy seed-containing food products cannot reliably be distinguished from codeine administration based on previously published urinary opiate concentrations and ratios. An important caveat is that in none of these cases did maximum urinary codeine concentrations exceed 1,300 ng/mL.
... Additionally, it should be remembered that synthetic opioids, such as fentanyl, are not readily detected with an in-office presumptive test. 36 ...
Objective:
Clinicians and policymakers have been wrestling with the appropriateness and safety of opioid therapy during the opioid crisis. Policy and clinical decisions have often been made without much current data on trends in drug use in patients with pain. Thus, we evaluated definitive urine drug test (UDT) results in patients being treated for pain to see if those taking their prescribed opioids were less likely to be positive for the primary illicit drugs currently driving overdose deaths: cocaine, heroin, fentanyl, and methamphetamine.
Design, setting, and patients:
A cross-sectional study of UDT results from January 1, 2015 to September 30, 2021, from 600,000 patient specimens submitted for testing by pain management specialists.
Interventions:
UDT by liquid chromatography-tandem mass spectrometry as ordered by the treating clinician.
Main outcome measures:
Presence of other substances stratified by whether a patient's prescribed opioid was found.
Results:
The presence of cocaine, heroin, fentanyl, and methamphetamine for the total population was low (<5 percent). Of the 347,092 patients prescribed opioids, 76 percent (n = 264,961) were positive on UDT for their prescribed opioid ("consistent"). Compared to patients without their prescribed opioid present ("inconsistent"), patients consistent with therapy were 54 percent (incidence rate ratio (IRR) 1.54, 95 percent confidence interval (CI) 1.47-1.59) less likely to be positive for cocaine, 47 percent [IRR 1.47, 95 percent CI 1.34-1.57] less likely to be positive for heroin, and 35 percent [IRR 1.35, 95 percent CI 1.24-1.45] less likely to be positive for methamphetamine, p < 0.001. Differences between the groups for fentanyl were not significant.
Conclusions:
Overall positivity rates for cocaine, heroin, fentanyl, and methamphetamine were low. Patients with prescribed opioid present were less likely to be positive for cocaine, heroin, or methamphetamine. Patterns of substance use within this pain management population should be used to inform ongoing policy decisions.
... Consumption of poppy seeds has been long reported to result in true opiate positives on urine drug screens [2]. The influence of poppy seed consumption on UDS results is especially relevant in the setting of chronic opioid management, where the screening and confirmation cutoffs are much lower than in the setting of workplace drug testing [3]. The trust underlying therapeutic relationships between patients and providers depends on reliable measures of opioid-use compliance, a notion that is central to the recommendations proffered by Argoff et al. [1]. ...
... Although the tests used in our study have excellent sensitivity and specificity, it is possible that some patients were misclassified based on the timing of the toxicology test or the substance used. 21 There is also significant debate in the literature about what age cut off or grouping should be used to define the elderly population. Different results may be obtained applying an age cut off that differs from that utilized in this study, and there certainly may be important additional subgroups with different risk factors and outcomes among the 55 and older population. ...
Background
Methamphetamine (METH) is associated with an elevated risk of injury and the outcomes in the elderly remain unclear. We analyzed METH's impact in elderly trauma patients.
Methods
Retrospective analysis (2009–2018) of trauma patients at a Level I trauma center. Elderly patients were defined as age ≥55. Substance use was identified by blood alcohol test and urine drug screen. Cox proportional hazard model was used to assess patient and injury characteristics with mortality.
Results
Of 15,770 patient encounters with substance use testing, 5278 (34%) were elderly. Elderly METH use quadrupled over time (2%–8%; p < 0.01). Elderly METH + patients were more likely to require surgical intervention (35% vs. 17%), mechanical ventilation (15% vs. 7%), and a longer hospitalization (6.5 vs. 3.6 days) compared with elderly substance negative. Multivariate analysis showed increasing age, ventilator use, and injury severity were associated with mortality (ps < 0.01); METH was not related to mortality.
Conclusion
Substance use in elderly trauma patients increased significantly. METH use in elderly trauma patients is a risk factor for significantly greater resource utilization.
... For instance, quinolones (e.g. moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, ciprofloxacin), rifampin, tolmetin (a non-steroidal anti-inflammatory drug) may yield a false-positive result in opiates urine drug screening (Reisfield, Goldberger, & Bertholf, 2009). Chloroquine pandemic, the clinicians should assess the benefits of the urinary or saliva testing at this critical circumstance, especially as this will potentially increase unnecessary risks due to close contacts. ...
The new coronavirus created a complex situation for all sections of the communities around the world. Health care
providers are in the frontline of intervening to stop the spread of COVID-19. Meantime people who use drugs (PWUD)
are at increased risk during this pandemic since they are a stigmatized and marginalized populations. Health service
providers who are providing different needs for PWUD in treatment and/or harm reduction settings should always
keep themselves safe with using standard PPE based on the WHO recommendations. Additionally PWUDs live in
crowded locations and so screening and early identification of COVID-19 patients are important to break the cycle
of transmission. It is recommended that protocols for opioid substitution therapy modify with complete adherence to
patients' safety regarding both opioid drug risks and COVID-19 infections. It is important to have in mind that different
stages of OST needs different approaches. PWUDs are more vulnerable to stress and other mental health problems.
This makes psychological interventions such as cognitive-behavioral therapy and other modalities very important to
have for PWUDs during these difficult and challenging times to assist and sustain treatment. Medical conditions such
as respiratory illness, renal insufficiency, chronic pain and cardiovascular disorders are also important medical conditions
that should be addressed appropriately among PWUDs with COVID-19. Health service providers in both fields
of addiction treatment and COVID-19 treatment and prevention systems should be aware regarding special situations
arising in the overlap of drug use and COVID-19 illness.
... For instance, quinolones (e.g. moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, ciprofloxacin), rifampin, tolmetin (a non-steroidal anti-inflammatory drug) may yield a false-positive result in opiates urine drug screening (Reisfield, Goldberger, & Bertholf, 2009). Chloroquine pandemic, the clinicians should assess the benefits of the urinary or saliva testing at this critical circumstance, especially as this will potentially increase unnecessary risks due to close contacts. ...
... For instance, quinolones (e.g. moxifloxacin, lomefloxacin, norfloxacin, ofloxacin, ciprofloxacin), rifampin, tolmetin (a non-steroidal anti-inflammatory drug) may yield a false-positive result in opiates urine drug screening (Reisfield, Goldberger, & Bertholf, 2009). Chloroquine pandemic, the clinicians should assess the benefits of the urinary or saliva testing at this critical circumstance, especially as this will potentially increase unnecessary risks due to close contacts. ...
Coronavirus disease 2019 (COVID-19) is escalating across the world with higher morbidities and mortalities in certain vulnerable populations. People who use drugs (PWUD) are a marginalized and stigmatized group with lower access to health care services, weaker immunity responses, vulnerability to stress, poor health conditions, and high-risk behaviors that put them at greater risk of COVID-19 infection and its complications. In this paper, an international group of experts on addiction medicine, infectious disease and disaster psychiatry explore the possible concerns raised and provide recommendations to manage the overlaps between COVID-19 and Substance Use Disorder (SUD).
... Common substances known to cause false-positive results on urine screening tests for drugs of abuse (DoA) include the Vicks inhaler testing positive for amphetamine, non-steroidal anti-inflammatory drugs such as ibuprofen testing positive for barbiturates, and cannabinoids and some fluoroquinolones testing positive for opiates. [8,9] Ma huang, a Chinese HM, caused a false-positive screening test for amphetamines, which was confirmed to be a cross-reaction of the ephedrine in the product. [10] Another area of concern is adulteration of samples. ...
Abstract
Background: Commercial herbal medicines (CHMs) marketed as immune boosters are gaining wide popularity in
South Africa, in the absence of control and regulatory guidelines. These commercially packaged and labelled herbal
preparations, acquired in various retail outlets, are used without consulting either a conventional health provider or
a traditional health practitioner. Although they are indicated for immune-boosting purposes, they might exert many
other beneficial and unwanted effects on physiological systems. Platelets are crucial in haemostasis and important
for the immunological system. The aim was to investigate the effect of the CHMs used to strengthen the immune
system on the activity of human platelets.
Methods: Six CHMs commonly used as African traditional medicines in Pretoria, South Africa, were tested for their
effects on healthy, isolated human platelets, using a bioluminescence method. The tested herbal medicines were
Intlamba Zifo™, Maphilisa™ Herbal medicine, Matla™ African medicine for all diseases, Ngoma™ Herbal Tonic
Immune Booster, Stametta™ Body Healing Liquid, and Vuka Uphile™ Immune Booster and serial-diluted standards of
each from 10 to 10,000 times. The luminol-enhanced luminescence activity of the platelets was measured after
incubation with the herbal medicines and activation with phorbol myristate acetate (PMA) or N-formyl-methionylleucyl-
phenylalanine (fMLP).
Results: Five herbal medicines, namely Intlamba Zifo™, Maphilisa™ Herbal medicine, Matla™ African medicine for all
diseases, Stametta™ Body Healing Liquid, and Vuka Uphile™ Immune Booster exerted comparable weak inhibitory
effects on both PMA and fMLP-induced platelets, which were concentration dependent at high doses, and inversely
related to concentration at low doses. Intlamba Zifo™, Matla™ African medicine for all diseases, Stametta™ Body
Healing Liquid, and Vuka Uphile™ exhibited weak, but non-systematic stimulatory effects at low doses, which were
not statistically significant. Ngoma™ Herbal Tonic Immune Booster had weak, inhibitory effects at high doses and
weak stimulatory effects that were inversely related to concentration at low doses.
Conclusion: The findings suggest a potential beneficial role of the CHMs in the suppression of platelets’ reactivity
and in enhancing the immune system. Caution, however, should be exercised as platelet inhibition and stimulation
predispose to the risk of bleeding and thrombosis, respectively.
Keywords: African traditional medicine; herbal medicine; human platelets, Luminescence, PMA, fMLP
... Unfortunately, due to the lack of specificity, false positive results can occur and many medications showing a cross reaction with the immunoassay used in UDS have been reported in literature [1]. The majority of these false positives results stem from a similarity in the structure of the parent medication or one of its metabolites to the tested drug [2]. The best practice following a positive UDS involves confirmation with the mass spectrometry (MS) technique, such as gas chromatography-mass spectrometry (GS-MC) or liquid chromatography-tandem mass spectrometry: MS testing, however, is limited or not available in many hospitals [3]. ...
There has been only a few reports regarding aripiprazole causing false positive urine amphetamine drug screens, exclusively on children accidently ingesting aripiprazole. Herein, we present the first reported case of a 40 year old woman affected by Bipolar I Disorder, treated with aripirazole at therapeutic oral dose ranging from 15 mg/day to 30 mg/day, in the context of a depressive episode with mixed and psychotic features, showing a false positive urine amphetamine drug screen. We document the relationship between aripiprazole-dose, plasma concentration and amphetamines values in toxicologic urine examinations over time. Awareness of potential false positive urine amphetamine drug screens during aripiprazole treatment can condition therapeutic choices and prevent legal implications.
... For example, ibuprofen can cause false-positive test results for cannabis detection, pseudoephedrine and trazadone can cause false positives for amphetamines, and opiate detection can be triggered by poppy seeds. 4,8,9 False-negative UDT results can also be problematic. False negatives can occur because the cutoff level for the IA test is above the concentration of the drug in the sample (e.g., because of dilution, adulteration, or other reasons), because the test was intended only to detect certain compounds within a class, or because the window of detection is too narrow to detect drug use within a few days of testing. ...
Background
Urine drug testing techniques have different rates of false-positive and false-negative test results. However, clinicians may have highly varying perceptions of test accuracy and may compensate for perceived inaccuracy by incorporating other factors into their interpretation of observed test results. Thus, there is the potential for adverse consequences from decisions based on inaccurate test results or interpretation.
Methods
We surveyed 466 members of the American Society of Addiction Medicine to examine clinicians’ perceptions of the accuracy of 2 types of urine drug tests, immunoassay (IA) and liquid chromatography–tandem mass spectrometry (LC-MS/MS), and the extent to which behavioral and demographic factors influence the interpretation of test results. Participants read 4 brief vignettes describing positive and negative test results in hypothetical patients who differed along several dimensions (gender, age, race/ethnicity, comorbid mental disorder, court-ordered versus voluntary status, treatment compliance). Outcome variables include likelihood of renewed drug use, likelihood of test error, whether to request additional testing, and whether to report the violation to a probation officer.
Results
The strongest predictor of study outcomes was treatment compliance (consistent versus inconsistent attendance), as this was the only independent variable to generate effect sizes of medium strength. Significant effect sizes were also found for type of test used (IA versus LC-MS/MS), legal status (court-mandated versus voluntary), presence of a comorbid mental disorder, treatment history, and race, although effect sizes for these variables were small and less consistently observed.
Conclusions
These results highlight the potential for error in clinician judgments about urine drug testing. Not only were participants likely to underestimate the accuracy of “confirmatory” LC-MS/MS testing, but vignettes suggested that a number of historical and demographic factors may influence interpretation of test results.
... Ved urintestning med immunkemiske metoder er der en lang raekke udfordringer, som oftest stammer fra krydsreaktioner med endogene forbindelser eller med laegemidler. Det kan resultere i både falsk positive og falsk negative resultater [10,11]. Brugen af immunkemiske teknikker, uanset om de er fuldautomatiserede på et laboratorium eller benyttes som manuelle hurtigtest, medfører generelt en stor risiko for fejl og forringelse af patientsikkerheden, hvor de kritiske faktorer er mangel på konfirmatoriske analyser og postanalytiske fejltolkninger [12,13]. ...
The emergence of an increasing number of new psychoactive substances (NPS) on the drug market requires a paradigm shift in drug testing. Immunoassay screening needs to be replaced with highly specific and sensitive analytical methods based on chromatography and mass spectrometry to produce accurate results, promote health and patient safety and collect data on the prevalence of NPS use, impact on public health and clinical aspects of NPS in Denmark. Development and implementation of new analytical methods currently present a major challenge for both clinical and forensic laboratories.
... Common substances known to cause false-positive results on urine screening tests for drugs of abuse (DoA) include the Vicks inhaler testing positive for amphetamine, non-steroidal anti-inflammatory drugs such as ibuprofen testing positive for barbiturates, and cannabinoids and some fluoroquinolones testing positive for opiates. [8,9] Ma huang, a Chinese HM, caused a false-positive screening test for amphetamines, which was confirmed to be a cross-reaction of the ephedrine in the product. [10] Another area of concern is adulteration of samples. ...
Background. The prevalent use of African traditional medicine by the general public has been reported. With commercialisation and marketing, some of the herbal medicines (HMs) used are readily available over the counter, most of them promoted as immune boosters. These commercial HMs have not been taken through clinical trials and other tests that would validate their composition and safety, and other properties such as their effect on laboratory diagnostic tests. Objective. To investigate the cross-reactivity of selected HMs with commonly tested drugs of abuse (DoA) using a qualitative rapid urinalysis assay. Methods. The six HMs selected were bought from local pharmacies. A rapid urinalysis screening test was performed with the Instant View Multi-Drug of Abuse Test kit from Labstix Diagnostics. Drug-free urine (DFU) was pooled from samples donated by healthy volunteers. Urine samples that had tested positive for DoA were obtained from a pharmacology laboratory. Aliquots of the urine samples were spiked with the HMs in neat and diluted form, and tested at various time intervals. Results. The results for the DFU samples spiked with the HMs remained negative. There were no significant changes in pH or specific gravity of the samples. The results of samples that had tested positive for tetrahydrocannabinol (THC) were not altered by five of the HMs when spiked at 40% v/v. The HM Ngoma Herbal Tonic Immune Booster caused false-negative results for the THC test. Conclusion. An important finding is that the herbal mixture Ngoma Herbal Tonic Immune Booster caused false-negative results for the cannabinoid screening test. It adds to the list of substances that may be potential adulterants of urine for screening tests. © 2017, South African Medical Association. All rights reserved.
... However, the question remains to what extent these monitoring assays are able to detect sample adulteration. 12 There may be concentrations of adulterants that would be sufficient to produce a false-negative result in immunological tests for DOA, but cannot be detected with monitoring assays such as CEDIA Õ sample check. ...
Background:
The dilution or adulteration of urine is a serious problem in drugs of abuse (DOA) testing. Tests to identify adulteration are currently available. This study investigated the ability of the CEDIA® sample check to detect adulteration.
Methods:
Eight different DOAs were added to a urine sample obtained from a healthy, drug free subject: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, 3,4-methylenedioxyamphetamine, benzoylecgonine, D-amphetaminesulfate, ethyl-D-glucuronide, morphine sulfate, oxazepam, (-)-11-nor-9-carboxy-∆(9)-tetrahydrocannabinol. Urine samples were diluted to yield three samples of DOA concentrations close to general cut-offs as used in methadone treatment centers, by health authorities for psychological tests and in traffic medicine. Aspirin, citric acid, CrO3, H202, soap, sodium metaborate, Vitamin C, were added in three, HCl and NaOH in one, and NaN3 in two concentrations. All samples were measured with commercially available immunological assays shortly after sample preparation and 24 hours later. All samples were further analysed with the CEDIA® sample check reaction which may identify adulteration.
Results:
Oxidizing reagents (H2O2 or CrO3) are most effective in interfering in the measurement ofr benzoylecgonine, EDDP, ethyl-D-glucuronide and morphine sulfate. The measurement of (-)-11-nor-9-carboxy-∆(9)-tetrahydrocannabinol is affected by many adulterants. Adulteration with HCl and NaOH was identified with the sample check reaction. NaN3 generated false negative results for a number of DOAs.
Conclusions:
Urine samples with DOA concentrations above cut-offs can be successfully tampered with adulterants in a way which cannot be detected with the CEDIA® sample check assay.
... Several testing methods utilizing mass spectrometry technology are capable of determining the presence of specific compounds. Gas chromatography-mass spectrometry (GC-MS) has been used for chemical analysis since the 1970's [16][17][18][19] and is employed by many laboratories, particularly those involved with workplace drug testing. However, the newer liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods have become viable alternatives for urine substance analysis of clinical specimens [14,15,20]. ...
Background: Laboratory urine drug testing of patients on chronic opioid therapy requires providing a large test menu of medications commonly prescribed for this population as well as metabolites and illicit substances. It has been shown that liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the preferred method to analyze urine specimens for these substances. Purpose of the study: To describe the challenges and some of the techniques to validate the analytical procedures used to identify and quantify these medications and substances. Methods: Using data obtained from testing over one million specimens, the authors developed a proposed test menu. Potential isobaric interferences were established by using literature references. A list of potentially interfering medications was obtained by using the proposed test menu and the most commonly prescribed medications. Finally, criteria were designed to detect possible carryover. Results: The LC-MS/MS instrumentation eliminated all potential interferences and provided quantitative data over the test range needed to monitor these patients. Carryover could be eliminated by setting the carryover thresholds for each analyte. Conclusions: Reference laboratories utilizing LC-MS/MS technology to conduct urine drug testing for pain clinicians should employ specific techniques described in this study to develop an optimal test menu and validate procedures that include isolating retention times for isobaric compounds, identifying interfering substances including impurities in medicinal and illicit substance preparations, monitoring ion suppression, and avoiding carryover.
... This expansion is largely due to the introduction of chemometric techniques, which allowed multivariate data to be included, modeled and used for qualitative analysis [2]. Multivariate qualitative methods have been developed and applied in such fields as clinical, medicine, biology and chemistry [3][4][5][6]. In food field, analytical (mainly spectroscopy) and classification techniques have been successfully combined for food fraud detection, both adulteration [7][8][9][10][11]and authentication [11][12][13][14][15]. ...
A strategy for determining performance parameters of two–class multivariate qualitative methods was proposed. As case study, multivariate classification methods based on mid-infrared (MIR) spectroscopy coupled with the soft independent modelling of class analogy (SIMCA) technique for detection of hydrogen peroxide and formaldehyde in milk were developed. From the outputs (positive/negative/inconclusive) of the samples, which were unadulterated and adulterated at target value, the main performance parameters were obtained. Sensitivity and specificity values for the unadulterated and adulterated classes were satisfactory. Inconclusive ratios 12% and 21%, respectively, for hydrogen peroxide and formaldehyde were obtained. To evaluate the performance parameters related to concentration, Probability of Detection (POD) curves were established, estimating the decision limit, the capacity of detection and the unreliability region. When inconclusive outputs were obtained, two additional concentration limits were defined: the decision limit with inconclusive outputs and the detection capability with inconclusive outputs. The POD curves showed that for concentrations below 3.7 g L⁻¹ of hydrogen peroxide and close to zero of formaldehyde, the chance of giving a positive output (adulterated sample) was lower than 5%. For concentrations at or above 11.3 g L⁻¹ of hydrogen peroxide and 10 mg L⁻¹ of formaldehyde, the probability of giving a negative output was also lower than 5%.
... The POCT and the instrumental drug tests are immunoassays; the tests are limited to fewer drugs and these tests also produce false-positive and false-negative results. [12][13][14] On the other hand, the GC-MS and LC-MS/MS are confirmatory tests and provide definitive presence of the drug and their metabolites at low concentration cutoffs. In addition, there are various kinds of toxicology testing, such as workplace, forensic, performance enhancement, and criminal justice testing. ...
Toxicology testing in addiction medicine varies across the spectrum, yet remains a powerful tool in monitoring addictive patients. There are many reference laboratories offering toxicology testing, and physicians should have some understanding of laboratory, methodology, testing portfolio, and customer support structure to aid them in selecting the best toxicology laboratory for their patients. Consultation with a clinical pathologist/toxicologist in conjunction with the consideration of monitoring large numbers of illicit and psychoactive drugs in the addictive patient may provide important clinical information for their treatment.
... Drug testing programs are implemented in many jurisdictions to help achieve a drug-free work environment, especially for safety-sensitive professions such as the military forces, transportation industry, mining industry, and any other industries engaged in heavy machine operations [1][2][3]. Drug testing programs are also established to service law enforcement authorities [4,5], detect doping in sports [6,7], and facilitate treatment of clinical intoxication, harm minimization, and rehabilitation programs [8][9][10][11]. ...
Urine drug testing plays an important role in monitoring licit and illicit drug use for both medico-legal and clinical purposes. One of the major challenges of urine drug testing is adulteration, a practice involving manipulation of a urine specimen with chemical adulterants to produce a false negative test result. This problem is compounded by the number of easily obtained chemicals that can effectively adulterate a urine specimen. Common adulterants include some household chemicals such as hypochlorite bleach, laundry detergent, table salt, and toilet bowl cleaner and many commercial products such as UrinAid (glutaraldehyde), Stealth® (containing peroxidase and peroxide), Urine Luck (pyridinium chlorochromate, PCC), and Klear® (potassium nitrite) available through the Internet. These adulterants can invalidate a screening test result, a confirmatory test result, or both. To counteract urine adulteration, drug testing laboratories have developed a number of analytical methods to detect adulterants in a urine specimen. While these methods are useful in detecting urine adulteration when such activities are suspected, they do not reveal what types of drugs are being concealed. This is particularly the case when oxidizing urine adulterants are involved as these oxidants are capable of destroying drugs and their metabolites in urine, rendering the drug analytes undetectable by any testing technology. One promising approach to address this current limitation has been the use of unique oxidation products formed from reaction of drug analytes with oxidizing adulterants as markers for monitoring drug misuse and urine adulteration. This novel approach will ultimately improve the effectiveness of the current urine drug testing programs.
... 32 Adolescents who used medical marijuana had an earlier age of regular marijuana use, more marijuana abuse, and more dependence and conduct disorder symptoms compared with teens who had not used medical marijuana. 32 It is important, too, to obtain informed consent and draw up a controlled substance 33 ) Regular follow-up also provides an opportunity to assess symptom and functional improvement. If the patient fails to keep appointments and does not respond to efforts to address the problem, the marijuana recommendation may have to be rescinded. ...
Wastewater-based epidemiology (WBE) is an innovative method of analyzing substance use and human activity within a community by examining biomarker indicators from wastewater samples. This method has emerged as a new and effective tool in forensic science and evidence collection. WBE provides a potential source of evidence for conducting collective analyses of crime-related substances and for monitoring illicit substance use at the community level. The approach is based on the principle of tracking illicit substances in wastewater as they are excreted through urine and feces into the sewer system. The analysis of biomarkers from collected wastewater samples provides an opportunity to detect substance use quickly, anonymously and non-invasively. This provides a robust strategy for assessing trends in illicit drug use within communities and providing concrete data to support forensic investigations.
WBE has made a significant contribution to the field of forensic science, particularly in the monitoring of crime trends. Its ability to detect the consumption of illicit drugs in a specific area is a valuable tool for law enforcement agencies. In regions with high levels of drug trafficking, WBE can indirectly provide information on the frequency of specific substance use, market size, and distribution networks. This method can play a critical role in law enforcement operations, strategic planning, and the monitoring of criminal group activities. WBE offers substantial support to law enforcement agencies and forensic science experts in terms of tracking crime trends and assessing public health risks.
In conclusion, WBE is recognized as a novel and effective evidential tool in forensic science, with the potential to play an instrumental role in crime-fighting strategies. The data it provides for monitoring the use of illicit substances and understanding the dynamics of the drug market renders it a valuable tool in forensic science.
Enzyme‐linked immunosorbent assay (ELISA) is a common analytical tool for screening samples in forensic toxicology laboratories, but it can be susceptible to interferences. The analysis of paired blood and oral fluid samples from the same subject led to the identification of a false negative ELISA screen for benzoylecgonine (BE) in blood. Investigation demonstrated that the issue was only with the Neogen® BE assay, and sample dilution did not remedy the problem. Based on subsequent monitoring of ELISA screens in blood, the false negative anomaly has only been identified in one specimen, and the cause remains undetermined.
Altered mental status (AMS) is a syndrome posing substantial burden to patients in the intensive care unit (ICU) in both prevalence and intensity. Unfortunately, ICU patients are often diagnosed merely with syndromic labels, particularly the duo of toxic–metabolic encephalopathy (TME) and delirium. Before applying a nonspecific diagnostic label, every patient with AMS should be evaluated for specific, treatable diseases affecting the central nervous system. This review offers a structured approach to increase the probability of identifying specific causal etiologies of AMS in the critically ill. We provide tips for bedside assessment in the challenging ICU environment and review the role and yield of common neurodiagnostic procedures, including specialized bedside modalities of diagnostic utility in unstable patients. We briefly review two common etiologies of TME (uremic and septic encephalopathies), and then review a selection of high-yield toxicologic, neurologic, and infectious causes of AMS in the ICU, with an emphasis on those that require deliberate consideration as they elude routine screening. The final section lays out an approach to the various etiologies of AMS in the critically ill.
Introduction
Adolescent overdoses have been rising over the past decade. Emergency department (ED) visits for both acute overdoses and for adolescents in opioid withdrawal have risen post-COVID. Urine drug screens have poor utility in the ED but are routinely obtained for medical clearance and in the management of patients with substance use disorder. Our primary goal was to measure the sensitivity of the opiate urine drug assay over time in opioid-related presentations to the ED.
Methods
We reviewed ED presentations at all EDs within our health system that were directly related to opioids from 1/1/2014 to 12/31/2022. For each patient included over the time frame, we identified whether a urine drug screen was obtained and the results from this screen. The urine drug screen available at all sites was an enzyme-multiplied immunoassay with an opiate screen (morphine antibody), but no fentanyl screen. The percent positivity for each drug category on enzyme multiplied immunoassay technique testing was calculated. Chi-squared tests were used to compare positivity rates between years.
Results
Opiate positivity declined over the last 9 years. Positivity rates from 2020 to 2022 were 5% ± 2% vs 82% ± 6% from 2014 to 2019 ( P < 0.001) Performance of UDS also declined over time (76% from 2014 to 2019 vs 46% from 2020 to 2022; P < 0.001). UDS was more likely to be performed in patients after a suicide attempt or when presenting after illicit use (66% vs 38%; P = 0.004).
Conclusion
Opiate screen positivity decreased the last 9 years and may reflect wider use of fentanyl among this population starting in 2020.
Issue:
Hospital alcohol and/or other drug (AOD) testing is important for identifying AOD-related injuries; however, testing methods vary. This systematic review aimed to examine biological AOD testing methods from hospital-based studies of injured patients and quantify what proportion reported key information on those testing methods.
Approach:
Observational studies published in English from 2010 onwards involving biological AOD testing for injured patients presenting to hospital were included. Studies examining single injury causes were excluded. Extracted data included concentration thresholds for AOD detection (e.g., lower limits of detection, author-defined cut-offs), test type (e.g., immunoassay, breathalyser) and approach (e.g., routine, clinical discretion), timing of testing, sample type and the proportion of injured cases tested for AODs.
Key findings:
Of 83 included studies, 76 measured alcohol and 37 other drugs. Forty-nine studies defined blood alcohol concentration thresholds (ranging from 0 to 0.1 g/100 mL). Seven studies defined concentration thresholds for other drugs. Testing approach was reported in 39/76 alcohol and 18/37 other drug studies. Sample type was commonly reported (alcohol: n = 69/76; other drugs: n = 28/37); alcohol was typically measured using blood (n = 60) and other drugs using urine (n = 20). Studies that reported the proportion of cases tested (alcohol: n = 53/76; other drugs: n = 28/37), reported that between 0% and 89% of cases were not tested for alcohol and 0% and 91% for other drugs. Timing of testing was often unreported (alcohol: n = 61; other drugs: n = 30).
Implications and conclusion:
Variation in AOD testing methods alongside incomplete reporting of those methods limits data comparability and interpretation. Standardised reporting of testing methods will assist AOD-related injury surveillance and prevention.
Background
We aimed to report the preliminary xylazine prevalence among people who inject drugs (PWID) treated at a student-run free clinic in Miami, FL, USA and to identify characteristics associated with screening positive for xylazine.
Methods
A retrospective chart review of 59 patients presenting to a syringe services program (SSP) clinic in was conducted between April 27th and August 17th, 2023. We measured presence of xylazine with rapid visual immunoassay strips on patient urine samples.
Results
Xylazine was present in 55.9 % (33/59) of urine samples including 2 without detected opioids. Xylazine presence was significantly associated with unsheltered homelessness (p = 0.018), presence of wound(s) (p = 0.008), and testing positive for hepatitis C antibody (p = 0.014), fentanyl (p = 0.005) and MDMA (p = 0.002).
Conclusions
A high prevalence of xylazine in the Southeastern United States furthers evidence of the geographical spread of xylazine and rapidly evolving illicit drug supply. Widespread xylazine screening is urgently needed to inform people who inject drugs and to studyinterventions to minimize harms associated with xylazine.
New designer drugs, access to databases, and changing availability of samples for analysis have changed the face of modern forensic toxicology in recent years. Forensic Toxicology: Drug Use and Misuse brings together the latest information direct from experts in each sub-field of the discipline providing a broad overview of current thinking and the most innovative approaches to case studies.
The text begins with an in-depth discussion of pharmacoepidemiology, including information on the value of nationwide databases in forensic toxicology. The use and abuse of drugs in driving, sport and the workplace are then discussed by industry experts who are conducting case work in their field. Not only are new drug groups discussed (NPS), but also their constantly changing impact on drug legislation. Synthetic cannabinoids, khat and mephodrone are discussed in detail. Following a section devoted to legislation and defence, readers will find comprehensive chapters covering sample choice reflecting the increasing use of hair and oral fluid, and also the less commonly used sweat and nail analysis. New and old case examples are compared and contrasted in the final part of the book, which will enable readers to understand how drugs impact on each other and how the interpretative outcome of a case are dependent on many aspects.
From use of pharmaceutical drugs in a clinical setting, through smart drugs to new psychoactive drugs, this book documents the wide range in which drugs today are abused. This book will be an essential resource for postgraduate students in forensic toxicology, and for researchers in forensic toxicology laboratories who need the latest data and knowledge.
Chronic pain and prescription opioid use are prevalent among patients with end-stage kidney disease treated with hemodialysis. Vulnerabilities to complications from opioid use are high in this patient population, as shown in many recent, well-conducted, patient-oriented studies. Such studies have highlighted the need for a balanced approach to pain management in hemodialysis patients that includes careful assessment of the risks and benefits of opioid prescriptions in this population. In this article, we review the available literature and experience regarding opioid prescriptions among hemodialysis patients, discuss clinical implications, and outline ongoing research.
Pain can be subdivided into two groups. Acute pain is typically caused by nociception and associated with events such as acute illness, trauma, or surgery. Chronic pain persists for long periods of time and does not serve a useful purpose. Pain from cancer and a neuropathy are examples of chronic pain. Opioids are the most common drugs used to treat pain; however, other types of medications are used to treat neuropathic or functional pain. These include skeletal muscle relaxants, antidepressants, anticonvulsants, corticosteroids, psychostimulants, capsaicin, local or regional anesthetics, and ketamine. When these drugs are prescribed chronically, pain management testing becomes a component of patient care. Urine is the specimen of choice for pain management testing. Although the testing is not used to establish dosing regimens, it monitors drug compliance and the use of other drugs that may interact with the prescribed drugs.
Coronavirus disease 2019 (COVID-19) is escalating across the world with higher morbidities and mortalities in certain vulnerable populations. People who use drugs (PWUD) are a marginalized and stigmatized group with lower access to health care services, weaker immunity responses, vulnerability to stress, poor health conditions, and high-risk behaviors that put them at greater risk of COVID-19 infection and its complications. In this paper, an international group of experts on addiction medicine, infectious disease and disaster psychiatry explore the possible concerns raised and provide recommendations to manage the overlaps between COVID-19 and Substance Use Disorder (SUD).
Nonalcohol substance use is a robust correlate of suicide risk. However, few data exist regarding the degree to which nonalcohol substance use, as measured by objective indicators (e.g., urinalysis toxicology screen), is related to suicide risk. This study examined the associations of a multimodal assessment of nonalcohol substance use and multiple indicators of suicide risk. Overall, 168 acute care psychiatric inpatients participated and provided data spanning urinalysis toxicology screen and self-report instruments. Substance use per urinalysis toxicology screen and self-report was not related to current suicidal ideation severity. However, substance use per urinalysis toxicology screen was significantly associated with a suicide attempt history and suicidality as a primary reason for admission. Substance use is an important variable to consider in suicide risk conceptualization. Findings underscore the importance of leveraging, when possible, objective indicators of substance use (e.g., urinalysis toxicology screen) in suicide risk formulations.
Individuals who receive buprenorphine treatment for opioid use disorder in office-based settings may be at risk for, or have a history of, polysubstance use. Urine drug testing is an important clinical tool for monitoring medication adherence and patient stability; and screening for illicit drug use and dangerous drug-drug interactions. This article is intended to educate practitioners in office-based opioid treatment settings on selecting appropriate substances for a definitive drug testing panel that are known to be used concurrently, sequentially, or in combination with buprenorphine for opioid use disorder. It is also intended to educate such practitioners on selecting appropriate testing technology to reduce risks to the health and safety of patients prescribed buprenorphine for opioid use disorder. In developing this article, the author conducted a search from May 2018 through December 2017 of peer-reviewed and government-supported articles in electronic databases. The literature showed that several common substances are often abused in conjunction with certain other substances, increasing the risk of serious adverse events, including death.
Whether used on their own, concurrently, sequentially, or in combination, substances of abuse carry significant health risks. Definitive urine drug testing, given its high specificity and sensitivity, can accurately identify the use of specific prescription medications and illicit substances that, especially when taken with buprenorphine or other substances, may cause harm to a patient. When testing for buprenorphine and other opioids; sedatives, hypnotics, and anxiolytics; cocaine; amphetamines; and PCP and other club drugs, providers in office-based opioid treatment settings are strongly advised to use definitive urine drug tests as the primary testing methodology. In addition, practitioners must be able to identify all other substances that a patient may be consuming, taking into consideration the patient’s historical and current drugs of choice, given that concurrent use with buprenorphine or other substances may cause serious adverse events. This article highlights the pressing market demand for comprehensive, definitive urine drug testing at a more reasonable cost.
Background and purpose: Some people are eligible for psychiatric exemptions before or during military service. This study aimed to investigate the common and uncommon psychological and behavioral situation in applicants for driving license exempt from military service.
Materials and methods: In this cross-sectional study, the population included applicants for driving license with psychiatric disorders who were exempt from military service in Khuzestan, Lorestan and Ilam provinces, Iran 2015. The sample size was 585. Data were collected using the checklists provided by the medical commissions in The Law Enforcement Force of the Islamic Republic of Iran (NAJA) which was previously used by The General Department of NAJA with approval of the Ministry of Health. Data analysis was done in SPSS V21.
Results: Among the applicants for driving license, 326 suffered mental disorders during military service and were exempted from military service. The disorders with highest frequency among the patients were seizure (31.5%) and mood disorders (29.2%). Among these individuals, 14.9% were banned from obtaining driving license, 63% were allowed to renew that, and 22% received treatment for mental disorders. The decisions for the driving license of the latter group were made after the treatment.
Conclusion: Mood disorders were found to be the most prevalent psychiatric disorder among the applicants for driving license, so, necessary precautions should be taken when issuing or renewing the driving license to these people.
Keywords: exemption, military service, driving license, psychiatric disorders, Iran
The increase in opioid prescribing in many European countries over the last decade has raised concerns about associated diversion, overdose and mortality. Fentanyl is one of these synthetic opioids that is typically prescribed as a transdermal patch for pain that requires continuous pain relief and has been the focus of investigations due to reports of overdose and death.
We report a case series of 14 drug addiction treatment entrants who entered treatment in one service located in the region of Southern Denmark from August 2015 to December 2015 for smoking fentanyl patches. Clients presented with difficulties breathing and pains in the lungs. The clients had a history of past opioid use, including heroin. Relapses resulted in treatment disengagement.
Immunoassays for fentanyl were used in the service. In some cases, false negative results occurred. Clients' urine samples were subsequently analysed in a collaborating laboratory. Seven clients tested positive for fentanyl. One client was positive for both fentanyl and heroin. Analyses were also positive for other opioids and metabolites in six clients, predominantly codeine and oxycodone. Results from confirmatory analysis contributed to clearer insights into clients' drug histories, which facilitated personalised care plans consisting of opioid agonist therapy informed by confirmed drug use.
In Denmark, prescription levels of fentanyl are high, which has been accompanied by observations of diversion and smoking in a smaller population. In addition to revision of inappropriate prescribing to reduce diversion, we recommend increased reliance upon confirmatory drug analysis in the addiction treatment sector in Denmark.
New technologies are urgently required for reliable drug screening given a worldwide epidemic of prescription drug abuse and its devastating socioeconomic impacts on public health. Primary screening of drugs of abuse (DoA) currently relies on immunoassays that are prone to bias, and are not applicable to detect an alarming array of psychoactive stimulants, tranquilizers and synthetic opioids. These limitations impact patient safety when monitoring for medication compliance, drug substitution or misuse/abuse, and require follow-up confirmatory testing by more specific yet lower throughput instrumental methods. Herein, we introduce a high throughput platform for nontargeted screening of a broad spectrum of DoA and their metabolites based on multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS). We demonstrate that MSI-CE-MS enables serial injections of ten samples within a single run (< 3 min/sample), where multiplexed electrophoretic separations are coupled to high resolution MS with full-scan data acquisition. Unambiguous drug identification was achieved by four or more independent parameters, including co-migration with a deuterated internal standard or in silico prediction of electromigration behavior together with accurate mass and molecular formula, as well as MS/MS for confirmation. Acceptable precision was demonstrated for over 50 DoA at three concentration levels over four days (median CV = 13%, n=117) with minimal ion suppression, isobaric interferences, and sample carry-over (< 1%). This approach offers a rapid yet accurate method for simultaneous detection and identification of DoA at their recommended screening cut-off levels in human urine while allowing for systematic surveillance, specimen verification and retrospective testing of designer drugs that elude conventional drug tests.
Clinical drug monitoring has an increasingly important role in the treatment of substance use disorders. Through semistructured interviews, we asked substance-use counselors about the clinical impact of drug tests on patients' treatment planning and outcomes. This study was conducted around the time of a facility-wide switch to a laboratory utilizing definitive liquid chromatography with tandem mass spectrometry from a laboratory that had utilized the less-sensitive, presumptive immunoassay-based drug-testing methodology. Twelve counselors volunteered to be interviewed, and each counselor chose 2 patients to discuss. Counselors reported that the facility-wide switch to definitive drug testing revealed some patients with newly identified relapses and substance use. They also reported that, as a result of the new information provided by definitive liquid chromatography with tandem mass spectrometry monitoring, 75% of the patients they discussed had a change made to their treatment plan, 79% were provided enhanced education, and 63% had an increase in their treatment intensity. Counselors also reported that 58% of these patients reduced their illicit drug and nonmedical prescription medication use as a result of treatment changes associated with the newly implemented definitive testing. Improvements in therapeutic relationships and honesty were also reported. These preliminary data are consistent with previous data and guidelines, suggesting that the results of definitive drug monitoring inform clinical decision-making and can help clinicians enhance treatment outcomes.
Despite the fact that chronic pain and
addiction often coexist, few pain training programs
offer significant experiential and didactic training in
drug abuse and addiction. Similarly, addiction medicine
programs often offer little training in pain management.
What follows is a review of the intersection
between these two specialties from the perspective
of clinicians that practice both.
Drug-related laboratory test interference or drug/laboratory test interactions (DLTI) is a major source of laboratory errors. DLTI is of concern with regard to both the clinical diagnosis and the monitoring of patients. Although there have been numerous reports about specific drugs that interfere with laboratory tests, there has not been a recent review on the topic. We herein provide a review of the known DLTI of U.S. FDA-approved drugs based on a systematic search of DailyMed, a website containing the labels of U.S. FDA-approved drugs. The labels for all human single-ingredient prescription drugs included in the database (1,368) were searched using stemmed keywords, and were manually reviewed for their relevance to DLTI. A total of 134 labels were positive, which indicated that the drug interferes with at least one clinical laboratory test. Antibacterial agents, psychotropic drugs, and contrast media are the classes of drugs most likely to lead to DLTI. Urine was the clinical sample most frequently affected by DLTI. The FDA drug label is a source of information for studies of DLTI, although information is still lacking for most drugs, and additional improvements are needed for many of the existing records. Medical professionals, clinicians and laboratory staff should keep these possible interactions in mind when interpreting the results of laboratory tests, and should ensure that they obtain a complete and accurate record of all drugs being used by patients in order to anticipate potential DLTI. The development of a reporting system to address potential DLTI is warranted.
Little is known about the types and outcomes of testing process errors that occur in primary care.
To describe types, predictors and outcomes of testing errors reported by family physicians and office staff.
Events were reported anonymously. Each office completed a survey describing their testing processes prior to event reporting.
243 clinicians and office staff of eight family medicine offices.
Distribution of error types, associations with potential predictors; predictors of harm and consequences of the errors.
Participants submitted 590 event reports with 966 testing process errors. Errors occurred in ordering tests (12.9%), implementing tests (17.9%), reporting results to clinicians (24.6%), clinicians responding to results (6.6%), notifying patient of results (6.8%), general administration (17.6%), communication (5.7%) and other categories (7.8%). Charting or filing errors accounted for 14.5% of errors. Significant associations (p<0.05) existed between error types and type of reporter (clinician or staff), number of labs used by the practice, absence of a results follow-up system and patients' race/ethnicity. Adverse consequences included time lost and financial consequences (22%), delays in care (24%), pain/suffering (11%) and adverse clinical consequence (2%). Patients were unharmed in 54% of events; 18% resulted in some harm, and harm status was unknown for 28%. Using multilevel logistic regression analyses, adverse consequences or harm were more common in events that were clinician-reported, involved patients aged 45-64 years and involved test implementation errors. Minority patients were more likely than white, non-Hispanic patients to suffer adverse consequences or harm.
Errors occur throughout the testing process, most commonly involving test implementation and reporting results to clinicians. While significant physical harm was rare, adverse consequences for patients were common. The higher prevalence of harm and adverse consequences for minority patients is a troubling disparity needing further investigation.
A 41-year-old African-American woman was admitted to an inpatient hospice facility with advanced, inoperable cervical cancer. The patient was experiencing severe pain secondary to extensive local tumor invasion, osseous pelvic metastases, and sacral decubitus ulcers. Her pain was treated with an escalating-dose schedule of morphine sulfate until satisfactory analgesia was achieved with stable doses of a combination of controlled-release morphine sulfate (MSContin®, Purdue Pharma LP) 400 mg orally every 8 h, and immediate-release morphine sulfate (MSIR®, Purdue Pharma LP), 180 mg orally every 4 h, as needed for breakthrough pain (average 2 to 3 doses per day). The patient experienced several episodes of life-threatening vaginal bleeding for which she was hospitalized for red blood cell transfusions and bilateral hypogastric artery embolizations. She spent the final 12 weeks of her life exclusively on the inpatient hospice unit. Approximately 3 weeks before her death, the patient underwent urine specimen collection and analysis of morphine and metabolites. GC-MS analysis revealed the presence of morphine as well as small quantities of hydromorphone.
During the past 2 decades, chronic opioid analgesic therapy (COAT) for chronic nonmalignant pain has gained increasing clinical acceptance. An unintended consequence of more liberal opioid prescription practices has been a dramatic increase in the abuse and diversion of these drugs.
According the most recent National Survey on Drug Abuse and Health (1), the number of new, past-year abusers of prescription opioids was 2 147 000—more than the number of new abusers of any other single class …
Fourteen nonsteroidal anti-inflammatory drugs were evaluated for interference in EMIT and TDx assays for drugs of abuse. Only tolmetin demonstrated significant interferences in the EMIT assay. Urine samples that contained high concentrations of tolmetin (1800 mg/L) had characteristic high molar absorptivity at the wavelength used in EMIT assays (340 nm). Consequently, EMIT analysis of samples resulted in instrument error alarms on a Hitachi 704 instrument and depressed milliabsorbance values (delta A) relative to calibrators. Similar results were obtained with urine samples collected from an arthritic patient after the administration of 200 and 400 mg of tolmetin. When tolmetin samples were mixed with drugs of abuse, depressed delta A values were noted in all assays. Samples containing opiates and cannabinoids tested negative, and instrument error alarms were produced with samples that contained amphetamines. A gas chromatographic-mass spectrometric (GC-MS) assay for benzoylecgonine in the presence of tolmetin was successful, and no interferences were noted. Similar interferences by tolmetin were not observed in TDx assays, probably because of the different wavelength (525 nm) used in this assay. However, a potential for false-positive results in the TDx benzodiazepine assay was noted for urine samples containing high concentrations of fenoprofen, flurbiprofen, indomethacin, ketoprofen, and tolmetin. Generally, it was concluded that the presence of tolmetin in urine samples could lead to the production of unacceptable results by the EMIT assay for drugs of abuse. However, TDx and GC-MS assays were useful alternatives for the analysis of urine samples suspected of containing tolmetin.
Proposed changes to the Health and Human Services Guidelines for forensic urine drug testing will lower the required cannabinoid immunoassay cutoff concentration from 100 to 50 micrograms/L. We investigated the effect of this change on the sensitivity, specificity, and efficiency of eight cannabinoid immunoassays: Syva Emit d.a.u. 100; Syva Emit II 100; Syva Emit d.a.u. 50; Syva Emit II 50; Roche Abuscreen Online; Roche Abuscreen radioimmunoassay; Diagnostic Reagents; and Abbott ADx. All specimens also were assayed by gas chromatography/mass spectrometry. Lowering the cutoff concentration from 100 to 50 micrograms/L increased efficiencies and sensitivities for all immunoassays, with minor decreases in specificity (1.0-2.6%). There was a 23.2-53.6% increase in the number of true-positive specimens identified. Thus, lowering the cannabinoid immunoassay cutoff concentration from 100 to 50 micrograms/L resulted in detection of a substantial number of additional true-positive specimens, with an accompanying small increase in unconfirmed positive results.
Interference by substances coeluting with targeted drugs is a general problem for gas chromatographic/mass spectrometric analysis of urine. To characterize these interferences, we examined human urine samples containing benzoylecgonine and fluconazole, and other drug combinations including deuterated internal standards that coelute (ISd,c) with target drugs, by selected-ion monitoring (SIM) and full-scan mass spectrometry. We show that, by SIM analysis, detecting the presence of an interferent is dependent on the specific IS used for the assay. When an ISd,c is used, the presence of another coeluting substance (interferent) suggests that the intensity of IS ions is substantially diminished, because the interferent affects both the ISd,c and target drug. When a noncoeluting IS (ISnc) is used, the interferent cannot be discerned unless it coincidently contains one or more of the ions monitored for either the target drug or ISnc. Under full-scan analysis, a coeluting interferent is directly discernable by examining the total ion gas chromatogram.
Testing for drugs of abuse in urine is commonplace in emergency departments and neonatal units. However, the clinical sensitivity of immunochemical screening methods is limited by the threshold concentrations used to distinguish between positive and negative specimens. Immunochemical screening methods for cocaine metabolite (benzoylecgonine), cannabinoids, and opiates in urine were recalibrated to detect drugs at lower threshold concentrations. The precision and linearity of the signals at the modified thresholds were verified by diluting drug-positive urine specimens to concentrations below the conventional cutoff concentration and measuring the rate signals in triplicate. To assess the clinical performance of the modified methods, specimens that tested negative using the unmodified assays were re-screened at the lower threshold, and specimens that re-screened positive were submitted for gas chromatographic/mass spectrometric (GC/MS) confirmation. Reproducibility of sub-threshold measurements was comparable to the unmodified assays, and rate separations between successive dilutions were sufficient to give semi-quantitative results. Using the lower thresholds, drugs were detected in 4-5% of the subjects that had screened negative at the conventional threshold concentration. GC/MS analysis confirmed the presence of cannabinoids and cocaine metabolite in 74% and 84%, respectively, of urine specimens that re-screened positive. Morphine, codeine, hydromorphone, or hydrocodone was detected by GC/MS analysis in 31% of opiate-positive re-screens.
Allegations of illicit hydrocodone use have been made against individuals who were taking physician-prescribed oral codeine but denied hydrocodone use. Drug detection was based on positive urine opiate immunoassay results with subsequent confirmation of hydrocodone by gas chromatography-mass spectrometry (GC-MS). In these cases, low concentrations of hydrocodone (approximately 100 ng/mL) were detected in urine specimens containing high concentrations of codeine (> 5000 ng/mL). Although hydrocodone has been reported to be a minor metabolite of codeine in humans, there has been little study of this unusual metabolic pathway. We investigated the occurrence of hydrocodone excretion in urine specimens of subjects who were administered codeine. In a controlled study, two African-American and three Caucasian male subjects were orally administered 60 mg/70 kg/day and 120 mg/70 kg/day of codeine sulfate on separate days. Urine specimens were collected prior to and for approximately 30-40 h following drug administration. In a second case study, a postoperative patient self-administered 960 mg/day (240 mg four times per day) of physician-prescribed oral codeine phosphate, and urine specimens were collected on the third day of the dosing regimen. Samples from both studies were extracted on copolymeric solid-phase columns and analyzed by GC-MS. In the controlled study, codeine was detected in the first post-drug-administration specimen from all subjects. Peak concentrations appeared at 2-5 h and ranged from 1475 to 61,695 ng/mL. Codeine was detected at concentrations above the 10-ng/mL limit of quantitation for the assay throughout the 40-h collection period. Hydrocodone was initially detected at 6-11 h following codeine administration and peaked at 10-18 h (32-135 ng/mL). Detection times for hydrocodone following oral codeine administration ranged from 6 h to the end of the collection period. Confirmation of hydrocodone in a urine specimen was always accompanied by codeine detection. Codeine and hydrocodone were detected in all specimens collected from the postoperative patient, and concentrations ranged from 2099 to 4020 and 47 to 129 ng/mL, respectively. Analyses of the codeine formulations administered to subjects revealed no hydrocodone present at the limit of detection of the assay (10 ng/mL). These data confirm that hydrocodone can be produced as a minor metabolite of codeine in humans and may be excreted in urine at concentrations as high as 11% of parent drug concentration. Consequently, the detection of minor amounts of hydrocodone in urine containing high concentrations of codeine should not be interpreted as evidence of hydrocodone abuse.
Urinary metabolic pattern after the therapeutic peroral dose of dihydrocodeine tartrate to six human volunteers has been explored. Using the GC-MS analytical method, we have found that the major part of the dose administered is eliminated via urine within the first 24 h. However, the analytical monitoring of dihydrocodeine and its metabolites in urine was still possible 72 h after the dose was administered. The dihydrocodeine equivalent amounts excreted in urine in 72 h ranged between 32 and 108% of the dose, on average 62% in all individuals. The major metabolite excreted into urine was a 6-conjugate of dihydrocodeine, then in a lesser amount a 6-conjugate of nordihydrocodeine (both conjugated to approximately 65%). The O-demethylated metabolite dihydromorphine was of a minor amount and was 3,6-conjugated in 85%. Traces of nordihydromorphine and hydrocodone were confirmed as other metabolites of dihydrocodeine in our study. This information can be useful in interpretation of toxicological findings in forensic practice.
Context.—Accurate specimen identification is critical for quality patient care. Improperly identified specimens can result in delayed diagnosis, additional laboratory testing, treatment of the wrong patient for the wrong disease, and severe transfusion reactions. Specimen identification errors have been reported to occur at rates of 0.1% to 5%.
Objective.—To determine the frequency of labeling errors in a multi-institutional survey.
Design.—Labeling errors were categorized as: (1) mislabeled, (2) unlabeled, (3) partially labeled, (4) incompletely labeled, and (5) illegible label. Blood specimens for routine or stat chemistry, hematology, and coagulation testing were included. Labeling error rates were calculated for each participant and tested for associations with institutional demographic and practice variable information.
Results.—More than 3.3 million specimen labels were reviewed by 147 laboratories. Labeling errors were identified at a rate of 0.92 per 1000 labels. Two variables were statistically associated with lower labeling error rates: (1) laboratories with current, ongoing quality monitors for specimen identification (P = .008) and (2) institutions with 24/7 phlebotomy services for inpatients (P = .02). Most institutions had written policies for specimen labeling at the bedside or in outpatient phlebotomy areas (96% and 98%, respectively). Allowance of relabeling of blood specimens by primary collecting personnel was reported by 42% of institutions.
Conclusions.—Laboratories actively engaged in ongoing specimen labeling quality monitors had fewer specimen labeling errors. Also, 24/7 phlebotomy services were associated with lower specimen error rates. Establishing quality metrics for specimen labeling and deploying 24/7 phlebotomy operations may contribute to improving the accuracy of specimen labeling for the clinical laboratory.
Context.—Emergency department physicians frequently request urine drug screens, but many are unaware of their limitations, including the potential for false-positive results. Promethazine, a phenothiazine derivative, is used for the treatment of allergies, agitation, nausea, and vomiting. Many patients taking promethazine are subject to urine drug screens and any potential interferences are important to recognize.
Design.—During an 11-month period, all patients presenting to the Massachusetts General Hospital emergency department who had a finding of promethazine in their serum drug screen, and who also had a urine drug screen performed, were selected for inclusion in the study. The urine drug screen results (n = 22 patients/samples) were then studied.
Objective.—To determine if promethazine use can cause false-positive urine amphetamine results in widely used drug of abuse immunoassays.
Results.—Thirty-six percent of patients taking promethazine had false-positive test results for urine amphetamines using the EMIT II Plus Monoclonal Amphetamine/Methamphetamine Immunoassay. Sixty-four percent of patients showed cross-reactivity greater than 20% higher than the blank calibrator rate. In a separate, related study, no promethazine-induced false-positive results were seen with the EMIT II Plus, Triage, and TesTcard 9 amphetamine assays, or the Triage methamphetamine assay. Reduced chlorpromazine interference was also seen with these other assays.
Conclusions.—False-positive urine amphetamine results can be obtained in patients taking promethazine. Promethazine metabolite(s), and not the parent compound, are the likely cause of these urine false-positive results obtained with EMIT II Plus Monoclonal Amphetamine/Methamphetamine Immunoassay. Immunoassays from different manufacturers can have very different “interference” profiles, which the pathologist and laboratory scientist must understand and relay to clinicians.
Context.—Patient safety is influenced by the frequency and seriousness of errors that occur in the health care system. Error rates in laboratory practices are collected routinely for a variety of performance measures in all clinical pathology laboratories in the United States, but a list of critical performance measures has not yet been recommended. The most extensive databases describing error rates in pathology were developed and are maintained by the College of American Pathologists (CAP). These databases include the CAP's Q-Probes and Q-Tracks programs, which provide information on error rates from more than 130 interlaboratory studies.
Objectives.—To define critical performance measures in laboratory medicine, describe error rates of these measures, and provide suggestions to decrease these errors, thereby ultimately improving patient safety.
Setting.—A review of experiences from Q-Probes and Q-Tracks studies supplemented with other studies cited in the literature.
Design.—Q-Probes studies are carried out as time-limited studies lasting 1 to 4 months and have been conducted since 1989. In contrast, Q-Tracks investigations are ongoing studies performed on a yearly basis and have been conducted only since 1998. Participants from institutions throughout the world simultaneously conducted these studies according to specified scientific designs. The CAP has collected and summarized data for participants about these performance measures, including the significance of errors, the magnitude of error rates, tactics for error reduction, and willingness to implement each of these performance measures.
Main Outcome Measures.—A list of recommended performance measures, the frequency of errors when these performance measures were studied, and suggestions to improve patient safety by reducing these errors.
Results.—Error rates for preanalytic and postanalytic performance measures were higher than for analytic measures. Eight performance measures were identified, including customer satisfaction, test turnaround times, patient identification, specimen acceptability, proficiency testing, critical value reporting, blood product wastage, and blood culture contamination. Error rate benchmarks for these performance measures were cited and recommendations for improving patient safety presented.
Conclusions.—Not only has each of the 8 performance measures proven practical, useful, and important for patient care, taken together, they also fulfill regulatory requirements. All laboratories should consider implementing these performance measures and standardizing their own scientific designs, data analysis, and error reduction strategies according to findings from these published studies.
Context Millions of assays are performed each year to monitor for substance
abuse in various settings. When common medications cross-react with frequently
used testing assays, false-positive results can lead to invalid conclusions.
Objective To evaluate cross-reactivity of quinolone antimicrobials in common opiate
screening assays and to assess the in vivo implications of this phenomenon.
Design, Setting, and Participants The reactivity of 13 quinolones (levofloxacin, ofloxacin, pefloxacin,
enoxacin, moxifloxacin, gatifloxacin, trovafloxacin, sparfloxacin, lomefloxacin,
ciprofloxacin, clinafloxacin, norfloxacin, and nalidixic acid) was tested
in 5 commercial opiate screening assays from September 1998 to March 1999.
In 6 healthy volunteers, we confirmed the cross-reactivity of levofloxacin
or ofloxacin with these opiate screening assays.
Main Outcome Measure Opiate assay activity (threshold for positive result, 300 ng/mL of morphine).
Results Nine of the quinolones caused assay results above the threshold for
a positive result in at least 1 of the assays. Four of the assay systems caused
false-positive results for at least 1 quinolone. Eleven of the 13 compounds
caused some opiate activity by at least 1 assay system. At least 1 compound
caused opiate assay activity in all 5 assay systems.
Levofloxacin, ofloxacin,
and pefloxacin were most likely to lead to a false-positive opiate result.
Positive results were obtained in urine from all 6 volunteers.
Conclusion Greater attention to the cross-reactivity of quinolones with immunoassays
for opiates is needed to minimize the potential for invalid test interpretation.
An electron-capture gas chromatographic procedure has been developed for the analysis of oxycodone in human urine, using naloxone
as internal standard. A major metabolite, tentatively identified as oxymorphone, was found to be excreted in conjugated form.
From 33–61% of a single oxycodone dose was excreted in the 24-hour urine of two subjects as free (13–19%) and conjugated oxycodone
(7–29%) and conjugated oxymorphone (13–14%). A second metabolite was observed by thin-layer chromatography, but was not identified.
Looks at drug use (and testing for it) in the workplace, and how it affects businesses. States, although drug users affect fellow workers through accidents at work, the non-users may also experience lowered morale. Directs employers how to introduce and operate drug testing programmes, listing six considerations. Concludes that once employers are aware of the legality of their actions they can perform drug testing programmes and provide both a drug-free workplace and a safe working environment.
Background:
Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively.
Methods:
Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis).
Results:
Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone; apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (S>R) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward.
Conclusions:
Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects.
The adulteration of urine samples is an ongoing problem in forensic drug-testing laboratories, even in the military where the practice of observed collections is performed. These adulterants are used to produce a false-negative result when samples are analyzed for drugs of abuse. It has been reported that papain, a cysteine protease, could be successfully used as a urine adulterant, altering the concentration of 11-nor-Delta9-tetrahydrocannabinol-9- carboxylic acid (THCCOOH) in urine samples. The current study analyzes the effects of latex papain (Sigma, 10 mg/mL) and Lawry's Adolph's Meat Tenderizer (papain is an active ingredient, 10 mg/mL) on immunoassays (FPIA, EMIT, KIMS) and gas chromatography-mass spectrometry (GC-MS) analysis for biological samples. The samples were analyzed initially between 2 and 4 h and then at 1-, 3-, 7-, and 10-day time intervals after the addition of papain. A decrease in response averaged over the course of the study was observed with FPIA (Abbott, 22%) and EMIT (Syva) Dade Behring, 26%, Microgenics, 10%) screening assays by the addition of latex papain to the samples. An increase in response was found using the KIMS (Roche) assay (156% increase). In addition, the GC-MS results (27% decrease) demonstrate that papain affects both the screening and confirmation assays. The addition of meat tenderizer caused decrease in the FPIA (Abbott, 11%) screening assay and GC-MS results (22%) similar to the latex papain while having varied results on the other screening assays. This study confirms papain could be a potential problem for urine drug-testing programs.
We observed cases of false-positive results with the use of liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Different LC-MS/MS techniques that use the selected reaction-monitoring mode, routinely employed for the analysis and quantification of drugs and toxic compounds in biological matrices, were involved in the false-positive and potentially false-positive results obtained. We sought to analyze the causes of and solutions to this problem.
We used a previously reported LC-MS/MS general unknown screening method, as well as manual spectral investigation in 1 case, to perform verification and identification of interfering compounds.
We observed that false-positive results involved: a metabolite of zolpidem that might have been mistaken for lysergic acid diethylamide, benzoylecgonine mistaken for atropine, and clomipramine and 3 phenothiazines that share several common ion transitions.
To prevent problems such as those we experienced, we recommend the use of stable-isotope internal standards when possible, relative retention times, 2 transitions or more per compound when possible, and acceptable relative abundance ratios between transitions, with an experience-based tolerance of +/-15% for transitions with a relative abundance >10% and with an extension to +/-25% for transitions <10% when the concentration is at the limit of quantification. A powerful general unknown screening procedure can help to confirm suspected interferences. Our results indicate that the specificity of screening procedures is questionable for LC-MS/MS analyses performed in the selected reaction-monitoring mode and involving a large number of compounds with only 1 transition per compound.
Hydrocodone (HC) has received renewed interest in the US due to reported increases in opiate related deaths involving psychotherapeutic drugs. The relative contribution of dihydrocodeine (DHC) in these deaths is unknown since little testing of this compound is performed. The objective of the study was to determine the prevalence of DHC in HC positive decedents and report the range of concentrations detected in these cases in order to evaluate the potential role of DHC in the deaths and determine the usefulness of including this analyte in opioid testing protocols. Specimens were assayed by liquid-liquid or solid phase extraction followed by gas chromatography/mass spectrometry operated in the selected ion monitoring mode. A multipoint calibration was utilized in the linear range 2-600ng/mL. Accuracy for HC, DHC and hydromorphone (HM) was 101-106% and between day precision at 160ng/mL between 7% and 11%. One hundred and thirty six cases were identified with the majority male (62%) and white (83%). A search of HC positive cases identified 64 with DHC (47%). The range of HC concentrations was 9-3039ng/mL heart blood (n=43) and 42-12353ng/mL urine (n=21). DHC concentrations in these cases ranged 3-243ng/mL in heart blood and 5-1842ng/mL in urine. DHC/HC ratios ranged 0.00(7)-2.90 in blood (n=43), and 0.01-5.04 in urine (n=21) with 16% and 24% of these cases with ratios >0.50, respectively. HM was detected in only 9 HC cases with the majority positive in urine.
On-site drug screening devices are widely used today for their simple test procedures and instantaneous results. Among other devices, a Triage Drug of Abuse panel is considered to be highly reliable for its high specificity and sensitivity of abused drugs. Although it is known that a false positive amphetamine (AMP) result may be obtained from the urine samples containing putrefactive amines or ephedrine-related compounds, no clinical false negative methamphetamine results have been reported to date. However, a false negative Triage result was obtained from the urine of a fatal methamphetamine poisoning victim taking Vegetamine tablets. Further experimental analyses revealed that the cross-reactivity of methamphetamine and chlorpromazine metabolites, including nor-2-chlorpromazine sulfoxide, was the cause for a false negative Triage reaction for AMP. Forensic scientists and clinicians must be aware of the limitations of on-site drug testing devices and the need for the confirmatory laboratory tests for the precise identification and quantification of drugs in suspicious intoxication cases, as also recommended by the manufacturers.
Benzodiazepines are currently among the most frequently prescribed drugs all over the world. They act as anxiolytics, sedatives, hypnotics, amnesics, antiepileptics and muscle relaxants. Despite their common chemical scaffold, these drugs differ in their pharmacokinetic and metabolic properties. In particular, they are biotransformed by different cytochrome P450 isoforms and also by different UDP-glucuronosyltransferase subtypes. The most important studies on the metabolic characteristics of several 1,4-benzodiazepines, carried out from 1998 onwards, are reported and briefly discussed in this review. Moreover, the analytical methods related to these studies are also described and commented upon and their most important characteristics are highlighted. Most methods are based on liquid chromatography, which provides wide applicability and good analytical performance granting high precision, accuracy and feasibility. Mass spectrometry is gaining widespread acceptance, particularly if the matrix is very complex and variable, such as human or animal blood. However, spectrophotometric detection is still used for this purpose and can grant sufficient selectivity and sensitivity when coupled to suitable sample pre-treatment procedures. A monograph is included for each of the following benzodiazepines: alprazolam, bromazepam, brotizolam, clotiazepam, diazepam, etizolam, flunitrazepam, lorazepam, midazolam, oxazepam and triazolam.
Accurate specimen identification is critical for quality patient care. Improperly identified specimens can result in delayed diagnosis, additional laboratory testing, treatment of the wrong patient for the wrong disease, and severe transfusion reactions. Specimen identification errors have been reported to occur at rates of 0.1% to 5%.
To determine the frequency of labeling errors in a multi-institutional survey.
Labeling errors were categorized as: (1) mislabeled, (2) unlabeled, (3) partially labeled, (4) incompletely labeled, and (5) illegible label. Blood specimens for routine or stat chemistry, hematology, and coagulation testing were included. Labeling error rates were calculated for each participant and tested for associations with institutional demographic and practice variable information.
More than 3.3 million specimen labels were reviewed by 147 laboratories. Labeling errors were identified at a rate of 0.92 per 1000 labels. Two variables were statistically associated with lower labeling error rates: (1) laboratories with current, ongoing quality monitors for specimen identification (P = .008) and (2) institutions with 24/7 phlebotomy services for inpatients (P = .02). Most institutions had written policies for specimen labeling at the bedside or in outpatient phlebotomy areas (96% and 98%, respectively). Allowance of relabeling of blood specimens by primary collecting personnel was reported by 42% of institutions.
Laboratories actively engaged in ongoing specimen labeling quality monitors had fewer specimen labeling errors. Also, 24/7 phlebotomy services were associated with lower specimen error rates. Establishing quality metrics for specimen labeling and deploying 24/7 phlebotomy operations may contribute to improving the accuracy of specimen labeling for the clinical laboratory.
Selegiline (R(-)-N-methyl-N-(1-phenyl-2-propyl)-2-propinylamine), a selective MAO-B inhibitor used as an antiparkinsonian, is excreted in urine as N-desmethyl selegiline (norselegiline), R(-)-methamphetamine (R(-)-MA), R(-)-amphetamine (R(-)-AM) and their conjugated p-hydroxy derivatives. We found that the fluorescence polarization immunoassays (FPIA) TDx amphetamine/methamphetamine II (AM/MA II) and TDx amphetamine class (AM class) lead to positive results for up to 2 days after a single oral dose of 10 mg selegiline (detection limit: 0.1 mg/l, each). Every urine specimen from long term selegiline patients (10 mg/day) showed positive TDx results during the selegiline regimen. Positive TDx results were confirmed using gas chromatography-mass spectrometry (GC-MS). Selegiline metabolites, particularly MA, could be detected in urine for up to 7 days after intake of a single oral dose of 10 mg selegiline (detection limit: 0.01 mg/l for MA and AM). Norselegiline, the only specific selegiline metabolite, was only detectable for about 12 h. Moreover, norselegiline was not detected in all urine samples from long term selegiline patients (10 mg/day). Since differentiation of selegiline intake from MA/AM abuse by detecting norselegiline was not possible in most cases, an enantioselective GC-MS procedure was developed. It allowed differentiation of the enantiomers of the selegiline metabolites and thereby separation of selegiline intake (only R(-)-enantiomers) from methamphetamine and/or amphetamine abuse (racemates or S(+)-enantiomers). After derivatization with S(-)-N-trifluoroacetyl-prolyl chloride (TPC), the two enantiomers of MA and AM were each separated as diastereomers employing the routinely used achiral GC capillary.(ABSTRACT TRUNCATED AT 250 WORDS)
Derivatives of seven commonly used sympathomimetic amines and two "designer amines" were isolated from urine, separated chromatographically from amphetamine and methamphetamine, and determined by mass spectrometry with selected ion monitoring. The drugs included ephedrine, propylhexedrine, pseudoephedrine, phenylpropanolamine, hydroxynorephedrine, phenylephrine, phentermine, methylenedioxyamphetamine (MDA), and methylenedioxy methamphetamine (MDMA). The drugs were liquid extracted from urine and derivatized by either heptafluorobutyric anhydride (HFBA) or 4-carbethoxyhexafluorobutyryl chloride (4-CB). Because the base peak ions for ephedrine, pseudoephedrine, propylhexedrine, MDMA, and phentermine are identical to methamphetamine (e.g. 254 amu for HFBA) and those for phenylephrine, hydroxynorephedrine, phenylpropanolamine, and MDA are identical to amphetamine (e.g. 240 amu for HFBA), a table of selected ions was developed for all 11 drugs that distinguished amphetamine and methamphetamine from the sympathomimetic amines with either HFBA or 4-CB. The distinguishing ions rely on the ring structure of the different drugs and fragmentation associated with that structure. The 4-CB reagent partially derivatized the hydroxy-containing sympathomimetic amines, while the HFBA completely derivatized all the sympathomimetic amines. Furthermore, false positive results for the 4-CB reagent were found only for methamphetamine (20-2250 ng/mL of methamphetamine) when high concentrations (greater than 5 micrograms) of ephedrine or pseudoephedrine were present in the specimen. These results are related to a combination of injection port temperature and cleanliness of the injection port sleeve.
Anecdotal and uncontrolled studies have suggested that nonsteroidal anti-inflammatory drugs produce false-positive results in immunoassay urine tests for some drugs of abuse. This study was performed in 60 volunteers who took ibuprofen as either a single 400-mg dose, or 200 mg three times a day, or 400 mg three times a day, and in 42 patients taking ibuprofen, naproxyn, or fenoprofen in therapeutic regimens for more than 30 days. Of the 510 urines collected from 102 individuals during these dosage regimens, two gave false-positive tests for cannabinoid by enzyme-mediated immunoassay (EMIA), one after 1200 mg of ibuprofen in three divided doses for one day and one in a patient taking naproxyn on a chronic basis; none was falsely positive for benzodiazepines. Two urines were false-positive for barbiturates by fluorescence polarization immunoassay (FPIA), one in a patient taking ibuprofen and one in a patient taking naproxyn. These data, collected prospectively, demonstrate the small likelihood of a false-positive immunoassay test result for cannabinoids, benzodiazepines, or barbiturates after the acute or chronic ingestion of ibuprofen, or after the chronic ingestion of naproxyn or fenoprofen.
A case of a false negative THC metabolite confirmation by GC/MS is presented. A urine specimen testing positive by the EMIT d.a.u. Cannabinoid 100-ng assay was subjected to confirmation by a GC/MS procedure designed to detect the methyl derivative of 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH). No methylated THC-COOH was found. Analysis of the specimen by the TOXI-LAB Cannabinoids TLC procedure yielded a positive confirmation. Subsequent work-up of the specimen revealed a high concentration of ibuprofen, which is shown to interfere with the methylation of THC-COOH. Reanalysis of the specimen by GC/MS with an increased amount of methylating reagent yielded a positive result.
Codeine O-demethylation to its active moiety morphine was investigated in human liver microsomes from 1 poor and 5 extensive metabolizer subjects (debrisoquine-type of oxidation polymorphism). Apparent Km of the reaction in one extensive metabolizer's microsomes was 149 microM and Vmax 17.6 nmol X mg P-1 X hour-1 versus greater than 1 mM and 1.6 nmol X mg P-1 X hour-1 respectively in one poor metabolizer. In vitro morphine production was competitively inhibited by quinidine (Ki 15 nM), the selective inhibitor of cytochrome P-450 dbl/bufI. There was also an excellent correlation between dextromethorphan O-demethylation, a prototype reaction for cytochrome P-450 dbl/bufI activity, and codeine O-demethylation. These data allow to conclude that codeine bioactivation to morphine is dependent on the polymorphic monooxygenase known as cytochrome db1/bufI.
A methadone maintenance patient with a decreased plasma methadone level, possibly due to phenobarbital-induced acceleration of methadone biotransformation, experienced opioid withdrawal symptoms. This finding suggests that when phenobarbital is used with methadone the plasma methadone level must be monitored.
The contribution of cytochrome P450 2D6 (CYP2D6) to the formation of hydrocodone's active metabolite, hydromorphone, was examined in vitro and in vivo. Human liver microsomes prepared from an individual homozygous for the D6-B mutation of the CYP2D6 gene catalyzed this reaction at a negligible rate. Urinary metabolic ratios of hydrocodone/hydromorphone were highly correlated with O-demethylation ratios for dextromethorphan, an established marker drug of CYP2D6 activity (rs = 0.85; n = 18). The kinetics of hydrocodone after a single oral dose and its partial metabolic clearance to hydromorphone were investigated in five extensive metabolizers of dextromethorphan, six poor metabolizers, and four extensive metabolizers after pretreatment with quinidine, a selective inhibitor of CYP2D6 activity. The mean values for partial metabolic clearance by O-demethylation in the three groups were 28.1 +/- 10.3, 3.4 +/- 2.4, and 5.0 +/- 3.6 ml/hr/kg, respectively. No statistically significant phenotypic differences in physiologic measures were observed. However, over the first hour after dosing, the extensive metabolizers reported more "good opiate effects" and fewer "bad opiate effects" than poor metabolizers and extensive metabolizers in whom CYP2D6 was inhibited by quinidine. These data establish the importance of CYP2D6 in the formation of hydromorphone from hydrocodone and suggest that the activity of this enzyme may limit the abuse liability of hydrocodone.
The cross-reactivity of l-methamphetamine (l-desoxyephedrine) to the EMIT-d.a.u. class (EC) and EMIT-d.a.u. monoclonal amphetamine/methamphetamine (EM) assays was evaluated in urine specimens collected from six subjects using Vicks inhalers. The subjects were five men and a woman ranging from 27 to 47 years old. Four subjects used the inhaler as recommended by the manufacturer for five consecutive days; two subjects used double this dosage for three consecutive days. All urine voids were collected, totaling 132 specimens. All specimens were analyzed by the EC and EM assays. Specimens yielding a positive response were then analyzed by chiral and achiral gas chromatography/mass spectrometry (GC/MS). No specimen was positive by the EM assay, whereas 17 specimens yielded positive EC results. One subject for form the "as recommended" group had six positive specimens with maximum l-desoxyephedrine of 872 ng/ml. Both subjects using twice the recommended dosage had positive specimens, maximum l-desoxyephedrine of 1,560 ng/ml. No positive specimen contained > 200 ng/ml l-amphetamine.
The presence of salicylates in urine reduces the signal in Emit assays (Syva), potentially yielding false-negative drugs-of-abuse screening results. We demonstrate that the principal urinary metabolite of salicylate, salicyluric acid (SUA; 2-hydroxybenzoylaminoacetic acid), interferes with the measurement of NADH formed in the assay by reducing the molar absorptivity of NADH at 340 nm. Thus, for a given concentration of d.a.u. analyte the change in absorbance over the assay time interval is less in the presence of SUA. With the Emit cocaine assay on the Hitachi 704 analyzer, the rate of absorbance change (delta AR) monitored at 340 nm for a specimen containing approximately 270 micrograms/L benzoylecgonine (BE) was 57 +/- 1.9 mA/min without SUA and 29 +/- 2.7 mA/min with 5 g/L SUA (n = 20). In contrast, delta AR determined at 376 nm was 18.6 +/- 0.5 mA/min with and 17.9 +/- 0.8 mA/min without 5 g/L SUA (n = 20). Measuring the Emit assay signal at wavelengths where SUA has no absorbance (376 nm) eliminates the interference due to SUA while maintaining the precision of the assay near the cutoff concentration for BE (300 micrograms/L).
Recently, certain laboratories reported the presence of methamphetamine in several negative urine specimens. We have demonstrated an artifact peak, by SIM GC/MS, in negative urine specimens, that frequently matches the retention time and identity ion ratio criteria for methamphetamine. This peak resulted from the presence of high levels of pseudoephedrine (PS) or ephedrine (EP) and was produced after derivatization with 4-carbethoxyhexafluorobutyryl chloride (CB), heptafluorobutyric anhydride (HFB), and N-trifluoroacetyl-l-prolyl chloride (TFAP). Use of N-methyl trideuterated PS and two deuterated EP compounds in spiked samples provided additional proof that PS and EP can produce the artifact peak. The above results were achieved using a GC injection port temperature of 300 degrees C and low split and isothermal conditions. Thermal transformation in the injector is involved because lowering and raising the injector temperature results in the disappearance and subsequent reappearance of the artifact peak. Proof that the artifact peak is actually methamphetamine was provided by full-scan GC/MS data of the artifact peak produced after use of all three derivatizing reagents. GC/MS analysis has demonstrated that urine (65 specimens) with concentrations of PS or EP ranging from 100,000 to 1,100,000 ng/mL will test negative for methamphetamine, while the same specimens will trigger positive results by radioimmunoassay and the Emit monoclonal assay. Full-scan GC/MS of the CB derivative for PS and EP reveals what appears to be both mono- and diderivatized products. SIM analysis can differentiate between PS and EP in urine specimens because the relative amounts of mono- and diderivatized products are very different for PS than for EP.(ABSTRACT TRUNCATED AT 250 WORDS)
The possible cross-reactivity of l-methamphetamine (desoxyephadrine) to the Syva Emit II amphetamine/methamphetamine assay was evaluated in urine specimens
collected from seven subjects using Vicks inhalers. The subjects were six males and one female ranging from 24 to 47 years
of age. Four subjects used the inhaler every two waking hours for five consecutive days, while three subjects inhaled hourly
for three consecutive days. All urine voids were collected, totaling 150 specimens. All specimens were analyzed by the Emit
II assay on a Hitachi 717 automatic analyzer with s 1000-ng/mL d-methamphetamine cutoff calibrator. None of the inhaler specimens produced an Emit II response equal to or greater than the
cutoff calibrator; all were negative. Specimens producing the highest rates were further analyzed by chiral GC/MS. The highest
concentrations of l-methamphetamine were observed in urines from two subjects inhaling hourly: 1390, 1290, and 740 ng/mL. These specimens were
collected the evenings of the second and third day. When used as directed or even with double the daily dose, Vicks inhalers
did not cause false-positive results in urine tested with the Emit II Amphetamine/Methamphetamine assay.
During routine drug analysis with the Syva d.a.u. Emit immunoassays we observed a high frequency of urines with lower rates of changes in absorbance (delta A R) than the rate for a drug-free urine calibrator. Many of these urines contained salicylates. Among 40 urines with apparent salicylate concentrations between 15 and 420 mg/dL tested for benzoylecgonine (BE), 20 had delta A R < -4 (range +2 to -28 mA/min). The rates decreased with increasing salicylate: delta A R = -0.057 x (salicylate, mg/dL) -0.22 mA/min (r = 0.85, n = 40, P < 0.01). Urines from 100 control subjects (no salicylate) had mean +/- SD delta A R values of -1.05 +/- 2.2 mA/min (range +3 to -7; only two were < -4 mA/min). Although direct addition of salicylic acid (200 mg/dL) to urine specimens did not reproduce the negative bias, ingestion of aspirin (acetylsalicylic acid) did by -0.09 mA/min per 1 mg/dL (72.4 mumol/L) salicylate. Negative biases observed for other Emit d.a.u. assays after salicylate ingestion lead us to conclude that ingestion of therapeutic doses of aspirin may cause false-negative results for drug screens in urines by this technology.
We evaluated a new EMIT II monoclonal amphetamine/methamphetamine assay for screening human urine by comparing it with the EMIT d.a.u. monoclonal amphetamine/methamphetamine assay and a fluorescence polarization assay. The EMIT II assay has a cutoff of 1 mg/L d-methamphetamine. The EMIT II and EMIT d.a.u. assays were run on a BM/Hitachi 704 analyzer; for the fluorescence polarization assay we used a TDx analyzer. All EMIT II positive samples were also analyzed by the fluorescence polarization assay. We used gas chromatography/mass spectrometry (GC/MS) for confirmation of the presence of amphetamine or methamphetamine. Within-run CVs for the Level 1 (1 mg/L) and Level 2 (3 mg/L) calibrators for the EMIT II assay were 0.47% and 0.53%, respectively. Corresponding between-run CVs were 1.48% and 1.60%, respectively. Of the 1007 samples screened for amphetamines, 50 were positive by the EMIT d.a.u. assay; 21 samples (not a subset of the 50 samples) were positive by the EMIT II assay. However, 19 samples that tested positive by EMIT II also tested positive by the EMIT d.a.u. assay. Subsequent testing of the EMIT II positive samples by the fluorescence polarization assay detected in six positive samples. By means of chiral derivatization wer identified two specimens containing primarily l-isomers of amphetamine and methamphetamine. Sympathomimetic amines were identified in several of the samples not containing amphetamine or methamphetamine.
Cocaine is a widely abused drug and causes death from overdose. Benzoylecgonine, the major metabolite of cocaine in urine is usually confirmed after derivatization by gas chromatography/mass spectrometry to demonstrate cocaine abuse. Recently, Wu et al. demonstrated that fluconazole coelutes with benzoylecgonine after conversion to trimethylsilyl analogs and causes false-negative result in the confirmation test. However, fluconazole did not interfere with the screening assay using a enzyme multiplied immunoassay technique. We demonstrated that by converting benzoylecgonine to the corresponding pentafluoropropionyl derivative, the interference of fluconazole can be completely eliminated. The pentafluoropropionyl derivative of benzoylecgonine eluted at 14.7 min while the derivatized fluconazole eluted at 15.6 min. The mass spectral fragmentation pattern of derivatized benzoylecgonine was distinctively different from the mass spectral features of derivatized fluconazole in both electron ionization and chemical ionization mode of operation of mass spectrometers. The quantitation of benzoylecgonine in positive urine specimens has not affected when the specimens were supplemented with 50 micrograms/mL of fluconazole.
A large-scale study was conducted to determine whether lowering the initial testing and confirmation testing cutoffs in urine would significantly affect the positive rates for cocaine (COC) and marijuana (THC). Customary cutoffs for COC are 300 microg/L and 150 microg/L for initial testing (screening) and gas chromatography-mass spectrometry (GC-MS; confirmation), respectively; for THC, the usual respective cutoffs are 50 microg/L and 10 microg/L. By applying a screening cutoff of 100 microg/L for COC and lowering the GC-MS cutoff to 50 microg/L, the COC-positive rate increased from 1.2% to 2.1%. For THC, lowering the screening cutoff to 20 microg/L while leaving the GC-MS cutoff at 10 microg/L increased the THC-positive rate from 2.8% to 4.1%. These increases appear noteworthy.
The cross-reactivities of four quinolone antibiotics--ofloxacin, norfloxacin, ciprofloxacin, and nalidixic acid--toward the EMIT II Opiates enzyme immunoassay were examined. Drug-free urine was spiked with the individual drugs up to 5,000 mg/L. Only ofloxacin showed potential for causing a false-positive opiates immunoassay screening result (apparent morphine > 300 micrograms/L). The method produced a positive opiate result at an ofloxacin concentration of 200 mg/L, a 0.16% cross-reactivity. Three hospitalized patients taking therapeutic doses of ofloxacin all gave false-positive EMIT II Opiates urine screening results. Three patients taking norfloxacin and three patients taking ciprofloxacin gave true-negative urine screening results. False-positive results were also obtained from the urines of two volunteers who each consumed a single 400-mg ofloxacin pill.
Immunoassay methods are commonly used to screen for drugs of abuse and some prescription drug classes as part of drug-testing programs in clinical and forensic toxicology. Oxaprozin (Daypro) is a new nonsteroidal anti-inflammatory drug that is widely prescribed in North America and has been reported to cross-react for benzodiazepines in several different immunoassay methods. The first objective of this study was to characterize the immunoreactivity of oxaprozin standards over a wide concentration range when analyzed by the EMIT dau, Abbott FPIA, and BMC CEDIA urine benzodiazepine assays. The second objective was to measure the immunoreactivity of urine specimens obtained from 12 subjects after receiving a single oral dose (1200 mg) of oxaprozin. Urine oxaprozin standards were prepared in drug-free urine at seven concentrations ranging from 500 to 100,000 ng/mL. The standards gave presumptive positive benzodiazepine results between 5000 and 10,000 ng/mL (EMIT dau) and approximately 10,000 ng/mL (FPIA, CEDIA). With a 200-ng/mL cutoff for benzodiazepines in these assays, all 36 urine specimens collected from the 12 subjects gave positive results by EMIT and CEDIA, and 35 of 36 urine specimens were positive by FPIA. It was concluded that presumptive positive benzodiazepine results by these immunoassays may be due to the presence of oxaprozin or oxaprozin metabolites. It is recommended that all positive immunoassay screening tests for benzodiazepines be confirmed by another technique based upon a different principle of analysis.
In vitro adulterants are used to invalidate assays for urine drugs of abuse. The present study examined the effect of pyridinium chlorochromate (PCC) found in the product "Urine Luck".
PCC was prepared and added to positive urine controls at concentrations of 0, 10, 50, and 100 g/L. The controls were assayed for methamphetamine, benzoylecgonine (BE), codeine and morphine, tetrahydrocannabinol (THC), and phencyclidine (PCP) with the Emit II (Syva) and Abuscreen Online (Roche) immunoassays, and by gas chromatography/mass spectrometry (GC/MS). Two tests were also developed to detect PCC in urine: a spot test to detect chromate ions using 10 g/L 1,5-diphenylcarbazide as the indicator, and a GC/MS assay for pyridine. We tested 150 samples submitted for routine urinalysis, compliance, and workplace drug testing for PCC, using these assays.
Response rates decreased at 100 g/L PCC for all Emit II drug assays and for the Abuscreen morphine and THC assays. In contrast, the Abuscreen amphetamine assay produced apparently higher results, and no effect was seen on the results for BE or PCP. The PCC did not affect the GC/MS recovery of methamphetamine, BE, PCP, or their deuterated internal standards, but decreased GC/MS recovery of the opiates at both intermediate (50 g/L) and high (100 g/L) PCC concentrations and apparent concentrations of THC and THC-d3 at all PCC concentrations. Two of 50 samples submitted for workplace drug testing under chain-of-custody conditions were positive for PCC, whereas none of the remaining 100 specimens submitted for routine urinalysis or compliance drug testing were positive.
PCC is an effective adulterant for urine drug testing of THC and opiates. Identification of PCC use can be accomplished with use of a spot test for the oxidant.